Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design
- Nicholas A. Meanwell*Nicholas A. Meanwell*Phone: (609) 252-6195. E-mail: [email protected]Discovery Chemistry and Molecular Technologies Bristol-Myers Squibb Research and Development P.O. Box 4000, Princeton, New Jersey 08543-4000, United StatesMore by Nicholas A. Meanwell
Abstract

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
Introduction

Key Properties of Fluorine of Relevance to Bioisostere Design
| bond | bond length (Å) | van der Waals radius (Å) | van der Waals volume of atom (Å3) | total size (Å3) | electronegativity of the element | dipole moment μ (D) | π | bond dissociation energy (kcal/mol) |
|---|---|---|---|---|---|---|---|---|
| C–H | 1.09 | 1.20 | 7.24 | 2.29 | 2.20 | ∼−0.4 | 0 | 98.8 |
| C–F | 1.35 | 1.47 | 13.31 | 2.82 | 3.98 | 1.41 | 0.14 | 105.4 |
| C–Cl | 1.77 | 1.75 | 22.45 | 3.16 | 1.87 (CH3Cl) | 0.71 | 78.5 | |
| C═O | 1.23 | 1.52 | 14.71 | 2.73 | 3.44 | 2.33 (H2C═O) | CHO: −0.65 | 85 (π bond) |
| C–OH | 1.43 (CH3OH) | 1.52 | 14.71 | 3.44 | 2.87 (CH3OH) | –0.67 | 84.0 | |
| 1.48 (CH3 CH2OH) | 1.66 (CH3 CH2OH) | |||||||
| C–C≡N | 2.22 (HCN) | 3.92 (CH3CN) | –0.57 | |||||
| S═O | 1.44 (CH3SO2 CH3) | 1.52 | 14.71 | 3.44 | 4.44 (CH3SO2 CH3)(9) | CH3SO: −1.58 | ||
| CH3SO2: −1.63 |
Fluorine as a Bioisostere of the Hydrogen Atom in Alkyl Moieties
Developability Aspects Associated with Fluorination and the Size of the CF3 Moiety
| vdW volume (Å3) | A value (kcal/mol) | Taft Es value | biphenyl rotational interference value (kcal/mol)(14) | experimental biphenyl rotational B value (ΔG⧧rot, kcal/mol)(15) | inhibition of MMP-9 by 2/3 IC50 (nM)(16) | |
|---|---|---|---|---|---|---|
| H | 1.20 | 0 | ||||
| F | 13.3 | 0.15 | –0.46 | 4.6 | 4.4 | |
| Me | 21.6 | 1.70 | –1.24 | 9.7 | 7.4 | 1/10 |
| Et | 38.9 | 1.70 | –1.31 | 8.7 | 2/27 | |
| CF3 | 39.8 | 2.10 | –2.40 | 12.1 | 10.5 | 87/22 |
| iPr | 56.2 | 2.15 | –1.71 | 12.6 | 11.1 | 1800/4500 |
| tBu | >4.50 | –2.78 | 18.3 | 15.4 |

Fluorination as an Approach to Reducing Metabolism










| R | P110α IC50 (nM) | P110β IC50 (nM) | P110δ IC50 (nM) | P110γ IC50 (nM) | RLM clearance (μL/min/mg) | rat clearance in vivo (mL/min/kg) | |
|---|---|---|---|---|---|---|---|
| 28 | CH3 | 14 | 4400 | 330 | 430 | 77 | 39 |
| 29 | CF3 | 5 | 1200 | 290 | 250 | 29 | 10 |
Figure 1

Figure 1. Key drug–target interactions between 29 and the PI3Kα enzyme and conformational bias provided by an intramolecular O to S interaction.



*LipE = pIC50 – Log P.

| R | DPP-4 IC50 (nM) | rat clearance (mL/min/kg) | oral bioavailability (F, %)a | |
|---|---|---|---|---|
| 37 | CH2CH3 | 37 | 70 | 2 |
| 38 | CF2H | 29 | 66 | 39 |
| 39 | CF2CF3 | 71 | 58 | 61 |
| 40 | CF3 | 18 | 60 | 76 |
Dose = 1 mg/kg IV; 2 mg/kg PO.




| R | SEH IC50 (nM) | solubility (μg/mL) | |
|---|---|---|---|
| 57 | iPr | 1.17 | 2.60 |
| 58 | tBu | 2.44 | 0.02 |
| 59 | CF3 | 0.37 | 2.60 |
| 60 | CF3O | 0.36 | 22.5 |
| 61 | (CF3)2CF | 0.02 | 0.17 |
Figure 2

Figure 2. Atropoisomerism associated with 4-(perfluoropropan-2-yl)-1H-indazol-5-amine.
Scheme 1


Metabolic Activation of Fluoro-alkyl Derivatives
Scheme 2



2,2-Difluoro-1,3-benzodioxole Derivatives
Scheme 3



Fluorination of Alkyl Groups and Conformational Effects
Fluorine for Hydrogen in Alkyl Groups Proximal to Amines

| stabilization energy (kcal/mol) | |
|---|---|
| F | 0.5–1.0 |
| OH | 1.0–2.0 |
| OAc | 1.6 |
| NHAc | 1.8 |
| NH2 | 0.9–1.0 |
| NH3+ | 5.8 |
Figure 3

Figure 3. Preferred conformation of 82 at the GABAA receptor (A) and the GABAC receptor and the transaminase enzyme (B) deduced from an evaluation of 83 and 84.

Figure 4

Figure 4. Proposed active conformation of NMDA at the GluN2A and GluN2B receptors after analysis of 91 and 92.
Fluorine for Hydrogen in Alkyl Groups Proximal to Amides
Figure 5

Figure 5. Conformational preferences of N-acetyl-proline methyl ester (94) (A), N-acetyl-4-(R)-fluoro-l-proline methyl ester (95) (B), and N-acetyl-4-(S)-fluoro-l-proline methyl ester (96) (C).
Figure 6

Figure 6. Acetamide conformation of 94 depicting an n → π* interaction.



| R | R′ | thrombin Ki (nM) | |
|---|---|---|---|
| 105 | H | H | 0.6 |
| 106 | F | H | 0.37 |
| 107 | H | F | 110 |
| 108 | F | F | 3.6 |

Fluorine for Hydrogen in Alkyl Groups Proximal to Fluorine
Figure 7

Figure 7. Geometry of 1,1-difluoroalkanes (A), the 1,4-di-CF2 motif (B), and conformational preferences for 1,2-difluoro- (C) and 1,3-difluoro-alkanes (D).





Replacing Hydrogen by Fluorine in Aromatic Rings
Aryl Fluoride Derivatives and Metabolism


Scheme 4


Aryl Fluorides: Membrane Permeability and P-gp Recognition

Figure 8

Figure 8. Core structures of MMPs of N-phenylamides and benzamides examined in a PAMPA.



| R1 | R2 | BACE-1 IC50 (nM) | Papp (10–6 cm/s) | efflux ratio | pKa of conjugate acid | |
|---|---|---|---|---|---|---|
| 157 | H | H | 500 | 3.4 | 12 | 8.4 |
| 158 | F | H | 158 | 12 | 3.1 | 7.1 |
| 159 | H | CF3 | 134 | 0.13 | >10 | ND |
| 160 | F | CF3 | 241 | 39 | 0.6 | 6.9 |
Aryl Fluorides and Conformation of Proximal Substituents



Aryl Fluorination and Solubility

Fluorine Mimicry with Nitrogen-Based Lone Pairs of Electrons
Aromatic Fluoride and Azine Mimesis
Figure 9

Figure 9. Comparison of the dipole moments and vectors of difluorinated benzenes and azines.



| X | α1 Ki (nM) | α3 Ki (nM) | α1 efficacy (% chlordiazepoxide) | α3 efficacy (% chlordiazepoxide) | μ of core (D) | |
|---|---|---|---|---|---|---|
| 180 | N | 0.71 | 0.47 | 60 | 79 | 5.10 |
| 181 | C–H | 4.35 | 5.16 | 35 | 61 | 3.37 |
| 182 | C–F | 0.20 | 0.32 | 34 | 104 | 4.52 |

| X | calculated dipole (D) | measured pKa | measured Log D7.4 | |
|---|---|---|---|---|
| 183 | N | 3.37 (R = CH3) | 4.9 (R = H) | –0.2 (R = H) |
| 184 | C–H | 5.10 (R = CH3) | 6.9 (R = H) | 0.8 (R = H) |
| 185 | C–F | 4.52 (R = CH3) | 4.9 (R = H) | 0.9 (R = H) |
Structures were built and energy minimized using the Merck Molecular Mechanics Force Field (MMFF). The dipole values were extracted from an AM1 semiempirical calculation.

Figure 10

Figure 10. Key interactions between CHK1 kinase and 190 in the cocrystal structure.



Figure 11

Figure 11. Structures and cathepsin L inhibitory data for 195–204.
Nitrogen Lone Pair Mimesis by an Alkyl Fluoride
Figure 12

Figure 12. Proposed relationship between a piperazine lone pair of electrons and the fluorine atom of a 4-fluoropiperidine ring.

Flourination and Potency
Multipolar and Hydrogen Interactions of Fluorine with Proteins

Figure 13

Figure 13. Key interactions between inhibitor 218 and thrombin.

Figure 14

Figure 14. Key drug–target interactions between the CF3 substituent of 224 and the p53 protein.

Figure 15

Figure 15. Key drug–target interactions between inhibitor 227 and BTK.


The CF3 Moiety and Tetrel Bonding
Figure 16

Figure 16. Calculated energies of the σ-hole and π-hole associated with perfluorotoluene.
Figure 17

Figure 17. Key interactions between 234 and IDH2 in the cocrystal stucture.(110b)
Figure 18

Figure 18. Key interactions between 235 and the NmrA-like family domain containing protein 1 NMRAL1 in the cocrystal complex.(111)


| 236 | 237 | |
|---|---|---|
| R | CH3 | CF3 |
| ovine COX-1 IC50 | 27 nM | >100 μM |
| mouse COX-2 IC50 | 127 nM | 267 nM |


†Biochemical enzyme inhibition assay. ‡Cell-based HCV replicon assay.

| R | X | R1 | Pf DHODH IC50 (μM) | Pf 3D7 cells EC50 (μM) | |
|---|---|---|---|---|---|
| 241 (DSM12) | H | CH | H | >200 | >100 |
| 242 (DSM97) | H | CH | CH3 | 4.2 | 6.4 |
| 243 (DSM74) | H | CH | CF3 | 0.28 | 0.34 |
| 244 (DSM280) | CH3CH2 | CH | CF3 | 0.087 | 0.058 |
| 245 (DSM267) | CH3CF2 | CH | CF3 | 0.038 | 0.010 |
| 246 (DSM265) | CH3CF2 | CH | SF5 | 0.033 | 0.046 |
Figure 19

Figure 19. Proposed dipole interactions between 248 and Aurora A kinase leading to a conformational change in the DFG loop of the enzyme.

Fluorine and the Modulation of the Basicity of Amines

| R | pKa of conjugate acid | Ki PNMT (μM) | Ki α2 (μM) | PNMT selectivity | |
|---|---|---|---|---|---|
| 250 | CH3 | 9.29 | 0.017 | 1.1 | 65 |
| 251 | CH2F | 7.77 | 0.023 | 6.4 | 280 |
| 252 | CHF2 | 6.12 | 0.094 | 230 | 2400 |
| 253 | CF3 | 4.33 | 3.2 | >1000 | >310 |




| R | R′ | JAK3 IC50 (nM) | hERG binding (μM) | cLogP | |
|---|---|---|---|---|---|
| 265 | H | H | 1.3 | 13.4 | 2.8 |
| 266 | F | H | 1.7 | >100 | 2.7 |
| 267 | H | F | 0.3 | >100 | 2.7 |

N-CF3 Derivatives


| Gram-positive | Gram-negative | ||||
|---|---|---|---|---|---|
| R | S. aureus Smith | St. pneumoniae type III | E. coli NIHJ JC-2 | P. aeruginosa IID1210 | |
| 275 | CH3 | 0.78 | 3.13 | 0.05 | 6.25 |
| 276 | CF3 | 0.39 | 6.25 | 0.05 | 1.56 |

Fluorine and Carbonyl Bioisosterism
sp3 C–F as a C═O Bioisostere

Fluoro Alkenes and Aromatic Fluorides as C═O Bioisosteres
Figure 20

Figure 20. Dipole moments and vectors that illustrate isosterism between an amide moiety and fluorinated alkene derivatives that contrasts with simpler alkenes.
Examples of Fluorinated Alkenes As Amide Bioisosteres


| A1-A2-Ser3-Glu-Ile-Gln-Leu-Met-His-Asn10-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg20-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp30-Val-His-Asn-Phe-Val-Ala-NH2 | ||||
|---|---|---|---|---|
| X | R | binding affinity to opossum kidney (OK-1) cells (pKD) | cyclic AMP OK1 EC50 (nM) (intrinsic activity | |
| 289 | F | CH3 | 8.2 | 9.1 (0.6) |
| 290 | Cl | CH3 | 8.9 | 5.5 (1.0) |
| 291 | F | iPr | 8.9 | 4.4 (1.0) |
| 292 | Cl | iPr | 8.9 | 7.9 (1.0) |



Aromatic Fluorides as C═O Bioisosteres
Figure 21

Figure 21. Key interactions between and FVIIa and the benzamidine-based inhibitor 304.


Figure 22

Figure 22. Key drug–target interactions between 309 and the HCV NS5B polymerase protein.

Figure 23

Figure 23. Key drug–target interactions between MEK1 and inhibitor 314.


Figure 24

Figure 24. Structural overlays of 82 with 318 and 319 illustrating C–F and C═O mimicry.


Alkenyl Fluoride as an Enol Mimetic

Scheme 5

Scheme 6


The 1,1-Difluoro Alkene Moiety as a C═O Bioisostere
Figure 25

Figure 25. Isosteric relationship between formaldehyde and 1,1-difluoroethylene.
Scheme 7


Scheme 8


The CF2 Moiety as a C═O Bioisostere



Fluorinated Motifs as Amide, Sulfonamide, and Urea Mimetics
Trifluoroethylamine and Difluoroethylamine Derivatives
Figure 26

Figure 26. Incorporation of the CF3CH2NH motif in a polypeptide backbone in register (B) or in a partially retro-inverted configuration (C) that mimics the amide of a conventional polypeptide (A).
Figure 27

Figure 27. Functional aspects of the mimicry between an amide and a sulfonamide moiety and CF3CH2NH and CHF2CH2NH.

| R | cathepsin K IC50 (nM) | pKa | |
|---|---|---|---|
| 362 | CF3 | 0.9 | 1.3 |
| 363 | CF2CF3 | 2.4 | 1.8 |
| 364 | CH3 | 988 | 6.7 |
| 365 | CN | 30 | 0.7 |



RCF2CH2NHR′ as a Bioisostere of RSO2NHR′



Fluorinated Amines and Mimesis of Imide-like Motifs




N-CH(CF3)2 as a Sulfone Bioisostere

Fluorinated Motifs and Urea Bioisosterism
Figure 28

Figure 28. Bond angles and lengths that illustrate topological mimesis between a urea and a fluoroenamide.


Fluoroamides and Urea Bioisosterism
Figure 29

Figure 29. Calculated conformational preferences for α-fluoromethyl and α,α-difluoromethyl secondary amides.
Figure 30

Figure 30. Conformational preferences of the α-fluorinated enantiomers of 413 designed to illuminate the bound conformation.

Figure 31

Figure 31. Topologies and bond lengths associated with α-fluoro-substituted amides 416–418 and urea 419 in the solid state.

| MT1 (pKi) | MT2 (pKi) | |
|---|---|---|
| 424 | 9.34 | 9.02 |
| 425 | 9.7a | |
| 426 | ∼10 | ∼10 |
| 427 | 8.21 | 9.40 |
| 428 | 10.27 | 9.07 |
| 429 | 8.24 | 8.75 |
| 430 | 8.30 | 8.75 |
| 431 | 14.3 | 7.62 |
Data from an assay assessing binding to cell membranes using ligands that do not distinguish the receptor subtypes(183a)

C–F as a Carbinol (C–OH) Mimic
C–F as a C–OH Bioisostere in Nucleoside Analogues
Figure 32

Figure 32. Preferred conformation of a 2′-α-fluoro-substituted ribose compared with a 2′-β-fluoro substituted isomer and a 2′-β, 2′-α-difluoro-substituted ribose ring.

Figure 33

Figure 33. Key H-bonding interactions between a 2′-methyl ribose moiety (436) and the 2′-fluoro-2′-methyl homologue that is the ribose hallmark of 434.



| R | poly(U) IC50 (μM) | MIC (IP8203) (μg/mL) | |
|---|---|---|---|
| 440 | C═O | 0.1 | 4 |
| 441 | (R)-CHOH | 0.05 | 1 |
| 442 | (S)-CHOH | 6 | 32 |
| 443 | (R)-CHF | 0.06 | 0.25 |
| 444 | (S)-CHF | 0.5 | 8 |
Fluorinated Motifs and Alcohol/Thiol Bioisosterism
Figure 34

Figure 34. Intermolecular H-bond observed in the single-crystal X-ray structure of oxadiazole 449.

Figure 35

Figure 35. Illustration of the functional mimicry between RSH and RCF2H in P1 residues incorporated into 450 and 452.







CF2 as a Bioisostere of an Oxygen Atom
CF2 and Phosphate/Pyrophosphate Mimicry

| 473 | 474 | 475 | 476 | 477 | 478 | |
|---|---|---|---|---|---|---|
| X | O | CH2 | CCl2 | CF2 | CHF | C(OH)2 |
| pKa2 | 2.36 | 2.87 | <2.6 | <2.7 | ||
| pKa3 | 5.77 | 7.45 | 6.11 | 5.80 | 6.15 | 5.81 |
| pKa4 | 8.22 | 10.96 | 9.78 | 8.00 | 9.35 | 8.42 |
| PhOP(O)(OH)2 | PhCH2P(O)(OH)2 | PhCH(F)P(O)(OH)2 | PhCF2P(O)(OH)2 | |
|---|---|---|---|---|
| pKa2 | 6.22 | 7.72 | 6.60 | 5.71 |
Figure 36

Figure 36. Geometric parameters for the phosphate, phosphonate, and difluoromethylenephosphonate moieties.


CF2 as an Oxygen Bioisostere in Sulfonic Acids and Sulfonamides


| IC50 (nM) | pKa | ||
|---|---|---|---|
| 500 | PhCH2SO2NH2 | 630 | 10.5 |
| 501 | PhCHFSO2NH2 | 220 | 8.8 |
| 502 | PhCF2SO2NH2 | 58 | 7.7 |
| 503 | CH3SO2NH2 | 650 | 10.8 |
| 504 | CF3SO2NH2 | <2 | 6.3 |
CF2 as an Oxygen Bioisostere in Heterocycles





ArCF2CH3 and ArOR Bioisosterism
Figure 37

Figure 37. Proposed isosterism between anisole and (1,1-difluoroethyl)benzene.

| R | IC50 (nM) | % remaining in RLMs | |
|---|---|---|---|
| 526 | CH3O | 104 | 6 |
| 527 | CF3O | 1110 | 95 |
| 528 | CH3CH2 | 11 | <5 |
| 529 | CH3CF2 | 14 | 96 |

| R | X | induced human TGR5 EC50 (nM) | CLint human (μL/min/mg) | |
|---|---|---|---|---|
| 530 | OCH3 | CH | 137 | 96 |
| 531 | OCF3 | CH | 2.3 | 184 |
| 532 | CH2CH3 | CH | 9.2 | 238 |
| 533 | CF2CH3 | CH | 2.7 | 211 |
| 534 | CF2CH3 | N | 43 | 18 |
Fluorinated Alkoxy Moieties and Mimesis
Conformational Aspects of Fluorinated Alkoxy Moieties
Figure 38

Figure 38. Conformational aspects of anisole, PhOCF3, and PhOCHF2.
Developability Aspects of Fluorinated Alkoxy Moieties

| R | CH3/CF3 configuration | CRF-1 IC50 (nM) | intrinsic clearance in HLM (mL/min/kg) | |
|---|---|---|---|---|
| 535 | CH3 | R | 1.1 | 130 |
| 536 | CF3 | R | 6.5 | 30 |
| 537 | CHF2 | R | 0.46 | 22 |
| 538 | CHF2 | S | 1.0 | 62 |
Fluorination of Alkyl Phenyl Ethers and Conformation

Fluorine As a Nitrile Bioisostere

The SF5 Moiety
Figure 39

Figure 39. Comparison of the shapes of the CF3 and SF5 substituents.

*A negative value indicates that the negative end of the dipole vector is toward the substituent.
Figure 40

Figure 40. Proposed drug–target interactions between 554 and T. cruzi trypanothione reductase based on docking of the ligand into the active site of the enzyme.



Conclusion
Biography
Nicholas A. Meanwell
Nicholas A. Meanwell received his Ph.D. degree from the University of Sheffield and conducted postdoctoral studies at Wayne State University before joining Bristol-Myers Squibb in 1982. He has been associated with the discovery of BMY-433771, an inhibitor of respiratory syncytial virus fusion, the HIV-1 attachment inhibitor prodrug fostemsavir, the HIV-1 maturation inhibitor BMS-955176, and the marketed HCV inhibitors asunaprevir (NS3, Sunvepra), daclatasvir (NS5A, Daklinza), and beclabuvir (NS5B). He is the co-recipient of a 2014 PhRMA Research and Hope Award for Biopharmaceutical Industry Research and a 2017 ACS Heroes of Chemistry Award. He was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award and was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015.
Acknowledgments
I thank Professors Günter Haufe (University Münster) and Frédéric Leroux (University of Strasbourg) for sowing the seeds of this manuscript. Drs. Dinesh Vyas, Kap-Sun Yeung, and Professor Günter Haufe and two reviewers are thanked for their critical review of an early version of the manuscript, while Dr. Makonen Belema is thanked for reviewing all versions of the article.
| Abbreviations Used | |
| AML | acute myeloid leukemia |
| BACE-1 | β-site amyloid precursor protein cleaving enzyme 1 |
| BCP | [1.1.1]-bicyclopentane |
| BTK | Bruton’s tyrosine kinase |
| Cdk | cyclin-dependent kinase |
| CETP | cholesteryl ester transfer protein |
| CFTR | cystic fibrosis transmembrane regulator |
| CGRP | calcitonin gene-related peptide |
| CRF-1 | corticotropin releasing factor-1 |
| CSD | Cambridge Structural Database |
| CYP | cytochrome P enzyme |
| DFT | density functional theory |
| DHODH | dihydroorotate dehydrogenase |
| DIO | diet-induced obese |
| DPP-4 | dipeptidyl peptidase-4 |
| ET | endothelin |
| FAAH | fatty acid amide hydrolase |
| FAP | fibroblast activation protein |
| FKBP | FK506-binding protein |
| FLT3 | FMS-like tyrosine kinase 3 |
| F-OPA | fluorinated olefinic peptide nucleic acid |
| FXa | factor Xa |
| GABA | γ-aminobutyric acid |
| GSH | glutathione |
| hAR | human androgen receptor |
| hBRS-3 | human bombesin receptor subtype-3 |
| HCV | hepatitis C virus |
| HIV-1 | human immunodeficiency virus-1 |
| HLM | human liver microsomes |
| hPTH | human parathyroid hormone |
| 5-HT | 5-hydroxytryptamine (serotonin) |
| Hyp | 4-(R)-hydroxy-l-proline |
| IDH2 | isocitrate dehydrogenase 2 |
| IV | intravenous |
| LM | liver microsomes |
| MCHR1 | melanin concentrating hormone receptor 1 |
| MEK1 | MAP kinase kinase 1 |
| MEP | molecular electrostatic potential |
| MGAT | acyl-CoA:monoacylglycerol acyltransferase |
| MI | metabolite intermediate |
| MMP | matched molecular pairs |
| Mtb | Mycobacterium tuberculosis |
| MW | molecular weight |
| NMDA | N-methyl-d-aspartate |
| PAMPA | parallel artificial membrane permeability assay |
| PDB | Protein Data Bank |
| Pf | Plasmodium falciparum |
| P-gp | P-glycoprotein |
| PI3Kα | phosphatidylinositol-3 kinase-α |
| PNMT | phenylethanolamine N-methyltransferase |
| PPARγ | peroxisome proliferator-activated receptor-γ |
| PSA | polar surface area |
| QM | quantum mechanics |
| RLM | rat liver microsomes |
| SAR | structure–activity relationship |
| STS | steroid sulfatase |
| TGR5 | Takeda G-protein-coupled receptor 5 |
| WGA | wheat germ agglutinin |
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It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.(g) Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881– 1886, DOI: 10.1126/science.1131943[Crossref], [PubMed], [CAS], Google Scholar.4ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVOlt7rN&md5=f804876c801518e48d0bdb7d87b7fb1cFluorine in Pharmaceuticals: Looking Beyond IntuitionMueller, Klaus; Faeh, Christoph; Diederich, FrancoisScience (Washington, DC, United States) (2007), 317 (5846), 1881-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all phys. and adsorption, distribution, metab., and excretion properties of a lead compd. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on mol. conformation of the drug, has only recently begun. Here, we review exptl. progress in this vein and add complementary anal. based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.(h) Shah, P.; Westwell, A. D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem. 2007, 22, 527– 540, DOI: 10.1080/14756360701425014[Crossref], [PubMed], [CAS], Google Scholar.4hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFOjtr%252FI&md5=58bc1c42a7525b66772967543256a7d2The role of fluorine in medicinal chemistryShah, Poonam; Westwell, Andrew D.Journal of Enzyme Inhibition and Medicinal Chemistry (2007), 22 (5), 527-540CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)A review. The small and highly electroneg. fluorine atom can play a remarkable role in medicinal chem. Selective installation of fluorine into a therapeutic or diagnostic small mol. candidate can enhance a no. of pharmacokinetic and physicochem. properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a no. of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomog. (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chem. applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimize mol. properties.(i) Maienfisch, P.; Hall, R. G. The importance of fluorine in the life science industry. Chimia 2004, 58, 93– 99, DOI: 10.2533/000942904777678091[Crossref], [CAS], Google Scholar4ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjt1yisbs%253D&md5=0b770772370a49778e3927efc3ccd14cThe importance of fluorine in the life science industryMaienfisch, Peter; Hall, Roger G.Chimia (2004), 58 (3), 93-99CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)Fluorine-contg. compds. are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the no. of fluorinated org. mols. reaching com. status as crop protection products and pharmaceutical drugs has been obsd.: in 1978, ∼600 pesticides were known, but only approx. 25 (4%) contained fluorine. Today, fluorine-contg. compds. account for more than 17% of all com. available crop protection agents and many others are currently under development. The structures of the fluorine-contg. development compds. proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ∼8% of all synthetic drugs. Six years later already more than 1500 fluorine-contg. drugs were under development. Fluorine-contg. compds. have also been successful in the market-place, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac), Paroxetine (Paxil), Ciprofloxacin (Cipro) and Cisaprid (Propulsid). This success is mainly due to the fact that selectively fluorinated compds. can exhibit dramatically improved potency when compared to the non-fluorinated analogs. The incorporation of fluorine into a biol. active compd. alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chem. and metabolic stability, and the bioavailability. The pos. effects of fluorine on the biol. efficiency is outlined by three examples: in the chem. class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biol. activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem-difluorovinyl group results in a strong decrease of biol. activity. - 5(a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016, 116, 422– 518, DOI: 10.1021/acs.chemrev.5b00392[ACS Full Text.
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Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronol. and classified according to an assocn. with a particular clin. indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qual. conclusions in this article aim to promote innovative insights into drug development. - 6(a) Jeschke, P. The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem 2004, 5, 570– 589, DOI: 10.1002/cbic.200300833[Crossref], [CAS], Google Scholar.6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFeqtLw%253D&md5=1f684935456162dfcbccf8069a6fd397The unique role of fluorine in the design of active ingredients for modern crop protectionJeschke, PeterChemBioChem (2004), 5 (5), 570-589CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.(b) Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manage. Sci. 2010, 66, 10– 27, DOI: 10.1002/ps.1829[Crossref], [PubMed], [CAS], Google Scholar.6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFGrsb3K&md5=6c28bc5a824d268f64c33e05e9b63df8The unique role of halogen substituents in the design of modern agrochemicalsJeschke, PeterPest Management Science (2010), 66 (1), 10-27CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)A review. The past 30 years have witnessed a period of significant expansion in the use of halogenated compds. in the field of agrochem. research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochem. with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, esp. in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the no. of com. products contg. mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addn. to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochems. throughout the twenty-first century. A no. of these recently developed agrochem. candidates contg. halogen substituents represent novel classes of chem. compds. with new modes of action. However, the complex structure-activity relationships assocd. with biol. active mols. mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a mol. at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilization of halogens and their unique role in the design of modern agrochems., exemplified by various com. products from Bayer CropScience coming from different agrochem. areas. Copyright © 2009 Society of Chem. Industry.(c) Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16– 29, DOI: 10.1016/j.jfluchem.2014.06.014[Crossref], [CAS], Google Scholar.6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFCgu7%252FM&md5=7fe60bc6faa07bfd629833ce8911c488Successful fluorine-containing herbicide agrochemicalsFujiwara, Tomoya; O'Hagan, DavidJournal of Fluorine Chemistry (2014), 167 (), 16-29CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A review. Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-contg. compds. have made a significant contribution to the development of products for the agrochems. industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compds. are grouped by mode of action. A synthesis route is described for each compd. although the synthesis presented may not actually be the industrial process.(d) Jeschke, P. Latest generation of halogen-containing pesticides. Pest Manage. Sci. 2017, 73, 1053– 1056, DOI: 10.1002/ps.4540[Crossref], [PubMed], [CAS], Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjs1Oqsrw%253D&md5=ba3907b014cc806b92985351db88b1b0Latest generation of halogen-containing pesticidesJeschke, PeterPest Management Science (2017), 73 (6), 1053-1066CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)Agriculture is confronted with enormous challenges, from prodn. of enough high-quality food to water use, environmental impacts and issues combined with a continually growing world population. Modern agricultural chem. has to support farmers by providing innovative agrichems., used in applied agriculture. In this context, the introduction of halogen atoms into an active ingredient is still an important tool to modulate the properties of new crop protection compds. Since 2010, around 96% of the launched products (herbicides, fungicides, insecticides/acaricides and nematicides) contain halogen atoms. The launched nematicides contain the largest no. of halogen atoms, followed by insecticides/acaricides, herbicides and fungicides. In this context, fungicides and herbicides contain in most cases fluorine atoms, whereas nematicides and insecticides contain in most cases 'mixed' halogen atoms, for example chlorine and fluorine. This review gives an overview of the latest generation of halogen-contg. pesticides launched over the past 6 years and describes current halogen-contg. development candidates. © 2017 Society of Chem. Industry.
- 7(a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem., Int. Ed. 2013, 52, 8214– 8264, DOI: 10.1002/anie.201206566[Crossref], [CAS], Google Scholar.7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCrs7bI&md5=1dafdf60409a792e78d946731f6cc2b9Introduction of Fluorine and Fluorine-Containing Functional GroupsLiang, Theresa; Neumann, Constanze N.; Ritter, TobiasAngewandte Chemie, International Edition (2013), 52 (32), 8214-8264CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.(b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and tri-fluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015, 115, 826– 870, DOI: 10.1021/cr500277b .(c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules by transition metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 2015, 115, 931– 972, DOI: 10.1021/cr500257c .(d) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V. Polyfluorinated ethanes as versatile fluorinated C2-building blocks for organic synthesis. Chem. Rev. 2015, 115, 973– 1050, DOI: 10.1021/cr500465n[ACS Full Text.
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- 10(a) Park, K. B.; Kitteringham, N. R. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab. Rev. 1994, 26, 605– 643, DOI: 10.3109/03602539408998319[Crossref], [PubMed], [CAS], Google Scholar.10ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmslSqtbc%253D&md5=a766e575c62e197c3a03a4557273b9ddEffects of fluorine substitution on drug metabolism: Pharmacological and toxicological implicationsPark, B. Kevin; Kitteringham, Neil R.Drug Metabolism Reviews (1994), 26 (3), 605-43CODEN: DMTRAR; ISSN:0360-2532.A review with 112 refs. Physicochem. properties of fluorinated drugs, fluorine substitution effect on drug metab., and fluorinated compds. as enzyme inhibitors are discussed.(b) Murphy, C. D.; Sandford, G. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity. Expert Opin. Drug Metab. Toxicol. 2015, 11, 589– 599, DOI: 10.1517/17425255.2015.1020295[Crossref], [PubMed], [CAS], Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksFymt78%253D&md5=b5c542a9e9d7e3c246d4f24da4918f2bRecent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicityMurphy, Cormac D.; Sandford, GrahamExpert Opinion on Drug Metabolism & Toxicology (2015), 11 (4), 589-599CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: Fluorine's unique physicochem. properties make it a key element for incorporation into pharmacol. active compds. Its presence in a drug can alter a no. of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailability and how the effects obsd. are related to the physicochem. characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biol. systems for fluorinated drug prodn. is discussed. Expert opinion: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technol. for the manufg. scale and new reagents and methods are required to meet the demands for the prepn. of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to det. the nature of transformation products that may cause ecol. damage.
- 11(a) Meanwell, N. A. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem. Res. Toxicol. 2011, 24, 1420– 1456, DOI: 10.1021/tx200211v[ACS Full Text.
], [CAS], Google Scholar11ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptlCitLs%253D&md5=9ddcf6dc81bf8ab0441df5037979ff4eImproving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and SafetyMeanwell, Nicholas A.Chemical Research in Toxicology (2011), 24 (9), 1420-1456CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. The development of small mol. drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclin. profiling that have improved compd. triaging and altered the underlying reasons for compd. attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochem. properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by mols. with increased mol. wt. and higher overall lipophilicity. The preponderance of mols. expressing these properties is frequently a function of increased arom. ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochem. properties assocd. with marketed drugs, guidelines for drug design have been developed that are based largely on calcd. parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochem. properties of a mol. that are consistent with the potential for good oral absorption were initially defined by Lipinski, with addnl. insights allowing further refinement, while deeper analyses have explored the correlation with metabolic stability and toxicity. These insights have been augmented by careful analyses of physicochem. aspects of drug-target interactions, with thermodn. profiling indicating that the signature of best-in-class drugs is a dependence on enthalpy to drive binding energetics rather than entropy, which is dependent on lipophilicity. Optimization of the entropic contribution to the binding energy of a ligand to its target is generally much easier than refining the enthalpic element. Consequently, in the absence of a fundamental understanding of the thermodn. complexion of an interaction, the design of mols. with increased lipophilicity becomes almost inevitable. The application of ligand efficiency, a measure of affinity per heavy atom, group efficiency, which assesses affinity in the context of structural changes, and lipophilic ligand efficiency, which relates potency to lipophilicity, offer less sophisticated but practically useful anal. algorithms to assess the quality of drug-target interactions. These parameters are readily calcd. and can be applied to lead optimization programs in a fashion that helps to maximize potency while minimizing the kind of lipophilic burden that has been dubbed "mol. obesity". Several recently described lead optimization campaigns provide illustrative, informative, and productive examples of the effect of paying close attention to carefully controlling physicochem. properties by monitoring ligand efficiency and lipophilic ligand efficiency. However, to be successful during the lead optimization phase, drug candidate identification programs will need to adopt a holistic approach that integrates multiple parameters, many of which will have unique dependencies on both the drug target and the specific chemotype under prosecution. Nevertheless, there are many important drug targets that necessitate working in space beyond that which has been defined by the retrospective analyses of marketed drugs and which will require adaptation of some of the guideposts that are useful in directing lead optimization.(b) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564– 616, DOI: 10.1021/acs.chemrestox.6b00043[ACS Full Text
], [CAS], Google Scholar11bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVCrs7Y%253D&md5=aef48399fb698b5f958c1cc11e1d25aaImproving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug SpaceMeanwell, Nicholas A.Chemical Research in Toxicology (2016), 29 (4), 564-616CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The phys., biol., and toxicol. properties of a drug candidate are inextricably linked to its structure, and once a mol. has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biol. properties of a mol. from an anal. of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a mol. is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clin. trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective anal. of drug design practices over the past decade has focused attention on the perception that contemporary mols. are unnecessarily obese, burdened by high mol. wt. and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chem. community with practical guideposts to enhancing compd. quality in the drug design phase and which can readily be applied, a series of efficiency indexes have been proposed that attempt to define aspects of compd. quality in the context of a series of physicochem. parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a mol. on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compd. aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, mols. that fall into space beyond that assocd. with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clin. therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compd. quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success. - 12Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455[ACS Full Text
], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsrzM&md5=20d7a36b75501c02570744857c82f325Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug DiscoveryHuchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, KlausJournal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences. - 13Pettersson, M.; Hou, X.; Kuhn, M.; Wager, T. T.; Kauffman, G. W.; Verhoest, P. R. Quantitative assessment of the impact of fluorine substitution on P-glycoprotein (P-gp) mediated efflux, permeability, lipophilicity, and metabolic stability. J. Med. Chem. 2016, 59, 5284– 5296, DOI: 10.1021/acs.jmedchem.6b00027[ACS Full Text
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- 17Shaughnessy, M. J.; Harsanyi, A.; Li, J.; Bright, T.; Murphy, C. D.; Sandford, G. Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life. ChemMedChem 2014, 9, 733– 736, DOI: 10.1002/cmdc.201300490
- 18Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-guided drug design. MedChemComm 2013, 4, 631– 652, DOI: 10.1039/c2md20317k[Crossref], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkslWmur0%253D&md5=61c667aa6f5c24de3fe110f384f323bdMetabolism-guided drug designStepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.MedChemComm (2013), 4 (4), 631-652CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. Preclin. drug metab. studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chem. entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns assocd. with the formation of protein and/or DNA-reactive metabolites. Metab. studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compds. with increased resistance to metab. and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metab. studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P 450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small mol. drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chem. intervention strategies. This review will showcase case studies of metab.-guided drug design using literature and inhouse examples.
- 19Dossetter, A. G. A matched molecular pair analysis of in vitro human microsomal metabolic stability measurements for methylene substitution or replacements - identification of those transforms more likely to have beneficial effects. MedChemComm 2012, 3, 1518– 1525, DOI: 10.1039/c2md20226c
- 20(a) Stalford, A. C.; Maggs, J. L.; Gilchrist, T. L.; Park, B. K. The metabolism of 16-fluoroestradiols in vivo: chemical strategies for restricting the oxidative biotransformations of an estrogen receptor imaging agent. Steroids 1997, 62, 750– 776, DOI: 10.1016/S0039-128X(97)00116-5 .(b) Diana, G. D.; Rudewicz, P.; Pevear, D. C.; Nitz, T. J.; Aldous, S. C.; Aldous, D. J.; Robinson, D. T.; Draper, T.; Dutko, F. J.; Aldi, C.; Gendron, G.; Oglesby, R. C.; Volkots, D. L.; Reurnan, M.; Bailey, T. R.; Czerniak, R.; Block, T.; Roland, R.; Oppermand, J. Picornavirus inhibitors: trifluoromethyl substitution provides a global protective effect against hepatic metabolism. J. Med. Chem. 1996, 38, 1355– 1371, DOI: 10.1021/jm00008a014 .(c) DeGoey, D. A.; Chen, H.-J.; Cox, P. B.; Wendt, M. D. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J. Med. Chem. 2017, DOI: 10.1021/acs.jmedchem.7b00717
- 21(a) Ojima, I. Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies. J. Fluorine Chem. 2017, 198, 10– 23, DOI: 10.1016/j.jfluchem.2016.12.016[Crossref], [PubMed], [CAS], Google Scholar.21ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlGntw%253D%253D&md5=b421b53c8371829b4ca44bbec7980a0eStrategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studiesOjima, IwaoJournal of Fluorine Chemistry (2017), 198 (), 10-23CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chem. and chem. biol. studies. Novel 3'-difluorovinyltaxoids were strategically designed to block the metab. by cytochrome P 450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3'-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3'-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymn. assay, morphol. anal. by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR anal. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other anal. methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean anal. of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical soln. to this problem.(b) Kuznetsova, L.; Sun, L.; Chen, J.; Zhao, X.; Seitz, J.; Das, M.; Li, Y.; Veith, J. M.; Pera, P.; Bernacki, R. J.; Xia, S.; Horwitz, S. B.; Ojima, I. Synthesis and biological evaluation of novel 3′-difluorovinyl toxoids. J. Fluorine Chem. 2012, 143, 177– 188, DOI: 10.1016/j.jfluchem.2012.07.007[Crossref], [PubMed], [CAS], Google Scholar.21bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyku7bI&md5=175149f9c565c30d1eccbeeaad4c3f75Synthesis and biological evaluation of novel 3'-difluorovinyl taxoidsKuznetsova, Larissa; Sun, Liang; Chen, Jin; Zhao, Xianrui; Seitz, Joshua; Das, Manisha; Li, Yuan; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.; Xia, Shujun; Horwitz, Susan B.; Ojima, IwaoJournal of Fluorine Chemistry (2012), 143 (), 177-188CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A series of 3'-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metab. by cytochrome P 450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3'-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the crit. importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H < F < Cl < N3. Among the twenty five 3'-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymn. much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymn., indicating strong stabilization of microtubules. Mol. modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.(c) Ehrlichová, M.; Ojima, I.; Chen, J.; Václavíková, R.; Němcová-Fürstová, V.; Vobořilová, J.; Šimek, P.; Horský, S.; Souček, P.; Kovář, J.; Brabec, M.; Gut, I. Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 2012, 385, 1035– 1048, DOI: 10.1007/s00210-012-0785-4[Crossref], [PubMed], [CAS], Google Scholar21chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSgsL3M&md5=0fcb97f2eeead6bb7bb18902a7dfc30cTransport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cellsEhrlichova, Marie; Ojima, Iwao; Chen, Jin; Vaclavikova, Radka; Nemcova-Fuerstova, Vlasta; Voborilova, Jana; Simek, Petr; Horsky, Stanislav; Soucek, Pavel; Kovar, Jan; Brabec, Marek; Gut, IvanNaunyn-Schmiedeberg's Archives of Pharmacology (2012), 385 (10), 1035-1048CODEN: NSAPCC; ISSN:0028-1298. (Springer)Resistance of tumors to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumor uptake of taxanes and their rapid metab. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metab. and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metab. of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metab. of the novel taxanes which was therefore not responsible for their different sensitivity, the obsd. differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G2/M block of the cell cycle similar to paclitaxel, but lower at concns. by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumor cells.
- 22Mascitti, V.; Stevens, B. D.; Choi, C.; McClure, K. F.; Guimarães, C. R. W.; Farley, K. A.; Munchhof, M. J.; Robinson, R. P.; Futatsugi, K.; Lavergne, S. Y.; Lefker, B.; Cornelius, A. P.; Bonin, P. D.; Kalgutkar, A. S.; Sharma, R.; Chen, Y. Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 1306– 1309, DOI: 10.1016/j.bmcl.2011.01.088
- 23Barnes-Seeman, D.; Beck, J.; Springer, C. Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analysis. Curr. Top. Med. Chem. 2014, 14, 855– 864, DOI: 10.2174/1568026614666140202204242[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlt1WntbY%253D&md5=214858abeb71f16981842708115ddb61Fluorinated Compounds in Medicinal Chemistry: Recent Applications, Synthetic Advances and Matched-Pair AnalysesBarnes-Seeman, David; Beck, Jeremy; Springer, ClaytonCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (7), 855-864CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. In recent years, several new fluorinated functional groups have been employed in medicinal chem. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-contg. groups. In addn., we examine the application of some fluorinated functional groups that have recently been gaining popularity in drug discovery. We use matched-pair anal. to assemble aggregate data on the impact on potency of one of these groups, pentafluorosulfanyl, as compared to trifluoromethyl. We further used matchedpair anal. to identify some interesting effects on in vitro ADME properties of replacing H by F on certain moieties.
- 24Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.-H.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically stable tert-butyl replacement. ACS Med. Chem. Lett. 2013, 4, 514– 516, DOI: 10.1021/ml400045j[ACS Full Text
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- 26Chao, Q.; Sprankle, K. G.; Grotzfeld, R. M.; Lai, A. G.; Carter, T. A.; Velasco, A. M.; Gunawardane, R. N.; Cramer, M. D.; Gardner, M. F.; James, J.; Zarrinkar, P. P.; Patel, H. K.; Bhagwat, S. S. Identification of N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo-[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J. Med. Chem. 2009, 52, 7808– 7816, DOI: 10.1021/jm9007533
- 27Sanga, M.; James, J.; Marini, J.; Gammon, G.; Hale, C.; Li, J. An open-label, single-dose, phase I study of the absorption, metabolism, and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia. Xenobiotica 2017, 47, 856– 869, DOI: 10.1080/00498254.2016.1217100
- 28Liu, G.; Abraham, S.; Liu, X.; Xu, S.; Rooks, A. M.; Nepomuceno, R.; Dao, A.; Brigham, D.; Gitnick, D.; Insko, D. E.; Gardner, M. F.; Zarrinkar, P. P.; Christopher, R.; Belli, B.; Armstrong, R. C.; Holladay, M. W. Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 3436– 3441, DOI: 10.1016/j.bmcl.2015.07.023[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOktL7I&md5=e0af0933baacfafe789ab3f49aa26f55Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitorsLiu, Gang; Abraham, Sunny; Liu, Xing; Xu, Shimin; Rooks, Allison M.; Nepomuceno, Ron; Dao, Alan; Brigham, Daniel; Gitnick, Dana; Insko, Darren E.; Gardner, Michael F.; Zarrinkar, Patrick P.; Christopher, Ron; Belli, Barbara; Armstrong, Robert C.; Holladay, Mark W.Bioorganic & Medicinal Chemistry Letters (2015), 25 (17), 3436-3441CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Based on a putative binding mode of quizartinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clin. development, the authors have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compd. I in tumor xenograft model for further preclin. development.
- 29Sebhat, I. K.; Franklin, C.; Lo, M. M.-C.; Chen, D.; Jewell, J. P.; Miller, R.; Pang, J.; Palyha, O.; Kan, Y.; Kelly, T. M.; Guan, X.-M.; Marsh, D. J.; Kosinski, J. A.; Metzger, J. M.; Lyons, K.; Dragovic, J.; Guzzo, P. R.; Henderson, A. J.; Reitman, M. L.; Nargund, R. P.; Wyvratt, M. J.; Lin, L. S. Discovery of MK-5046, a potent, selective bombesin receptor subtype-3 agonist for the treatment of obesity. ACS Med. Chem. Lett. 2011, 2, 43– 47, DOI: 10.1021/ml100196d[ACS Full Text
], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht12lt7fK&md5=5c50e792b9a560ca33da2e9392a12ae1Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of ObesitySebhat, Iyassu K.; Franklin, Christopher; Lo, Michael M.-C.; Chen, David; Jewell, James P.; Miller, Randy; Pang, Jianmei; Palyha, Oksana; Kan, Yanqing; Kelly, Theresa M.; Guan, Xiao-Ming; Marsh, Donald J.; Kosinski, Jennifer A.; Metzger, Joseph M.; Lyons, Kathryn; Dragovic, Jasminka; Guzzo, Peter R.; Henderson, Alan J.; Reitman, Marc L.; Nargund, Ravi P.; Wyvratt, Matthew J.; Lin, Linus S.ACS Medicinal Chemistry Letters (2011), 2 (1), 43-47CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the development and characterization of compd. 22 (MK-5046), a potent, selective small mol. agonist of BRS-3 (bombesin receptor subtype-3). In pharmacol. testing using diet-induced obese mice, compd. 22 caused mechanism-based, dose-dependent redns. in food intake and body wt. - 30Furet, P.; Guagnano, V.; Fairhurst, R. A.; Imbach-Weese, P.; Bruce, I.; Knapp, M.; Fritsch, C.; Blasco, F.; Blanz, J.; Aichholz, R.; Hamon, J.; Fabbro, D.; Caravatti, G. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 2013, 23, 3741– 3748, DOI: 10.1016/j.bmcl.2013.05.007[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosFaisrY%253D&md5=a0d2d69e01e7a82a5fed04114105925eDiscovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluationFuret, Pascal; Guagnano, Vito; Fairhurst, Robin A.; Imbach-Weese, Patricia; Bruce, Ian; Knapp, Mark; Fritsch, Christine; Blasco, Francesca; Blanz, Joachim; Aichholz, Reiner; Hamon, Jacques; Fabbro, Doriano; Caravatti, GiorgioBioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3741-3748CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compds. in inhibiting PI3Kα, a medicinal chem. program has led to the discovery of the clin. candidate NVP-BYL719 I.
- 31(a) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A survey of the role of noncovalent sulfur interactions in drug design. J. Med. Chem. 2015, 58, 4383– 4438, DOI: 10.1021/jm501853m[ACS Full Text.
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], [CAS], Google Scholar31bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFart7rI&md5=7192e3b57e66fc6eb9dd53165427d449Intermolecular Sulfur···Oxygen Interactions: Theoretical and Statistical InvestigationsZhang, Xuejin; Gong, Zhen; Li, Jian; Lu, TaoJournal of Chemical Information and Modeling (2015), 55 (10), 2138-2153CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Intermol. S···O interactions are very common and are important in biol. systems, but until recently, the presence of these contacts in protein-ligand systems largely depended on serendipitous discovery instead of rational design. Here we provide insight into the phenomenon of intermol. S···O contacts by focusing on three sulfur-contg. arom. rings. Quantum mechanics is employed to characterize the strength and directionality of the S···O interactions and to det. their energy dependence on their geometric parameters. Protein Data Bank mining is performed to systematically det. the occurrence and geometry of intermol. S···O interactions, and several representative examples are discussed. Three typical cases are investigated using a combined quantum mechanics/mol. mechanics approach to demonstrate the potential of these interactions in improving binding affinities and physiochem. properties. Overall, our work elucidates the structures and energy features of intermol. S···O interactions and addresses their use in mol. design. - 32Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B. T.; Lai, A. G.; Setti, E.; Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L.; Struss, B.; Gibney, M.; Armstrong, R. C.; Gunawardane, R. N.; Nepomuceno, R. R.; Valenta, I.; Hua, H.; Gardner, M. F.; Cramer, M. D.; Gitnick, D.; Insko, D. E.; Apuy, J. L.; Jones-Bolin, S.; Ghose, A. K.; Herbertz, T.; Ator, M. A.; Dorsey, B. D.; Ruggeri, B.; Williams, M.; Bhagwat, S.; James, J.; Holladay, M. W. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J. Med. Chem. 2012, 55, 1082– 1105, DOI: 10.1021/jm2009925
- 33Pettersson, M.; Johnson, D. S.; Humphrey, J. M.; Butler, T. W.; am Ende, C. W.; Fish, B. A.; Green, M. E.; Kauffman, G. W.; Mullins, P. B.; O’Donnell, C. J.; Stepan, A. F.; Stiff, C. M.; Subramanyam, C.; Tran, T. P.; Cooper Vetelino, B.; Yang, E.; Xie, L.; Bales, K. R.; Pustilnik, L. R.; Steyn, S. J.; Wood, K. M.; Verhoest, P. R. Design of pyridopyrazine-1,6-dione γ-secretase modulators that align potency, MDR efflux ratio, and metabolic stability. ACS Med. Chem. Lett. 2015, 6, 596– 601, DOI: 10.1021/acsmedchemlett.5b00070[ACS Full Text
], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVaksrg%253D&md5=ba402f2e67fd9500123cbc7b215d3361Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic StabilityPettersson, Martin; Johnson, Douglas S.; Humphrey, John M.; Butler, Todd W.; am Ende, Christopher W.; Fish, Benjamin A.; Green, Michael E.; Kauffman, Gregory W.; Mullins, Patrick B.; O'Donnell, Christopher J.; Stepan, Antonia F.; Stiff, Cory M.; Subramanyam, Chakrapani; Tran, Tuan P.; Vetelino, Beth Cooper; Yang, Eddie; Xie, Longfei; Bales, Kelly R.; Pustilnik, Leslie R.; Steyn, Stefanus J.; Wood, Kathleen M.; Verhoest, Patrick R.ACS Medicinal Chemistry Letters (2015), 6 (5), 596-601CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochem. properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp3-character. The lead compd. I (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust redns. of brain Aβ42 and Aβ40 were obsd. in a guinea pig time-course expt. - 34Mukherjee, P.; Pettersson, M.; Dutra, J. K.; Xie, L.; am Ende, C. W. Trifluoromethyl oxetanes: synthesis and evaluation as a tert-butyl isostere. ChemMedChem 2017, 12, 1574– 1577, DOI: 10.1002/cmdc.201700333[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2jur%252FJ&md5=fec9231daeaa93fcf67e63cd74815060Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl IsostereMukherjee, Paramita; Pettersson, Martin; Dutra, Jason K.; Xie, Longfei; am Ende, Christopher W.ChemMedChem (2017), 12 (19), 1574-1577CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The synthesis of new trifluoromethyl oxetanes such as I [R = 4-CO2HC6H4, 2-MeOC6H4CH2, 5-CO2Et-2-thienyl, etc.] was developed using Corey-Chaykovsky epoxidn./ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displayed a broad substrate scope. A limitation to the epoxidn./ring expansion was obsd. when attempting to use a more sterically encumbered aryl trifluoromethyl ketone, the intermediate epoxide, 2-(trifluoromethyl)-2-(2,4,6-trimethylphenyl)oxirane was isolated. The trifluoromethyl oxetane was also evaluated as a tert-Bu isostere in the context of the γ-secretase modulator (GSM) program. The trifluoromethyl oxetane-contg. GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-Bu GSM analog was demonstrated, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-Bu isostere.
- 35(a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2005, 48, 141– 151, DOI: 10.1021/jm0493156[ACS Full Text.
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(American Chemical Society)A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (I) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclin. species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of I, was selected for development as a potential new treatment for type 2 diabetes.(b) Kim, D.; Kowalchick, J.E.; Edmondson, S. D.; Mastracchio, A.; Xu, J.; Eiermann, G. J.; Leiting, B.; Wu, J. K.; Pryor, K. D.; Patel, R. A.; He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate). Bioorg. Med. Chem. Lett. 2007, 17, 3373– 3377, DOI: 10.1016/j.bmcl.2007.03.098 .(c) Thornberry, N. A.; Weber, A. E. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr. Top. Med. Chem. 2007, 7, 557– 568, DOI: 10.2174/156802607780091028[Crossref], [PubMed], [CAS], Google Scholar35chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsFersrY%253D&md5=8221de915c797c517f6116acb9c03cd1Discovery of JANUVIA (sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetesThornberry, Nancy A.; Weber, Ann E.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2007), 7 (6), 557-568CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclin. validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compds. inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclin. species. Indeed, the obsd. toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chem. efforts focused on identifying a highly selective DPP-4 inhibitor for clin. development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivs. were prepd., culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclin. species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes. - 36Mayer, S. C.; Kreft, A. F.; Harrison, B.; Abou-Gharbia, M.; Antane, M.; Aschmies, S.; Atchison, K.; Chlenov, M.; Cole, D. C.; Comery, T.; Diamantidis, G.; Ellingboe, J.; Fan, K.; Galante, R.; Gonzales, C.; Ho, D. M.; Hoke, M. E.; Hu, Y.; Huryn, D.; Jain, U.; Jin, M.; Kremer, K.; Kubrak, D.; Lin, M.; Lu, P.; Magolda, R.; Martone, R.; Moore, W.; Oganesian, A.; Pangalos, M. N.; Porte, A.; Reinhart, P.; Resnick, L.; Riddell, D. R.; Sonnenberg-Reines, J.; Stock, J. R.; Sun, S.-C.; Wagner, E.; Wang, T.; Woller, K.; Xu, Z.; Zaleska, M. M.; Zeldis, J.; Zhang, M.; Zhou, H.; Jacobsen, J. S. Discovery of begacestat, a notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer’s disease. J. Med. Chem. 2008, 51, 7348– 7351, DOI: 10.1021/jm801252w[ACS Full Text
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- 38Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.; Claremon, D. A.; Elliott, J. M.; Freidinger, R. M.; King, S. A.; Libby, B. E.; McIntyre, C. J.; Pribush, D. A.; Remy, D. C.; Smith, G. R.; Tebben, A. J.; Jurkiewicz, N. K.; Lynch, J. J.; Salata, J. J.; Sanguinetti, M. C.; Siegl, P. K. S.; Slaughter, D. E.; Vyas, K. Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current IKs by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide. J. Med. Chem. 1997, 40, 3865– 3868, DOI: 10.1021/jm970517u
- 39(a) Tohnishi, M.; Nishimatsu, T.; Motoba, K.; Hirooka, T.; Seo, A. Development of a novel insecticide, flubendiamide. J. Pestic. Sci. 2010, 35, 490– 491, DOI: 10.1584/jpestics.J10-06[Crossref], [CAS], Google Scholar.39ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvFentA%253D%253D&md5=c30fd345f321bd82fc74a97143a0debcDevelopment of a novel insecticide, flubendiamideTohnishi, Masanori; Nishimatsu, Tetsuyoshi; Motoba, Kazuhiko; Hirooka, Takashi; Akira, SeoJournal of Pesticide Science (Tokyo, Japan) (2010), 35 (4), 490-491, 508-515CODEN: JPSTCF; ISSN:1348-589X. (Pesticide Science Society of Japan)Flubendiamide, a novel class insecticide possessing a unique chem. structure, was discovered by Nihon Nohyaku Co., Ltd., and was registered in Japan in 2007 under the trade name of Phoenix WDG. The compd. is not only the first example of 1,2-benzenedicarboxamide insecticides but also the first practical synthetic insecticide with a mode of action as an activator of ryanodine receptors. It shows high and selective activity against lepidopterous insect pests, which leads to excellent efficacy in the field and excellent safety against non-target organisms, including various beneficial arthropods and natural enemies. These properties suggested the suitability of flubendiamide for integrated pest management (IPM) programs.(b) Nakao, T.; Banba, S. Broflanilide: a meta-diamide insecticide with a novel mode of action. Bioorg. Med. Chem. 2016, 24, 372– 377, DOI: 10.1016/j.bmc.2015.08.008[Crossref], [PubMed], [CAS], Google Scholar39bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVajsrzN&md5=4e4ee18a96c5e975e623b8bc7d058ce9Broflanilide: A meta-diamide insecticide with a novel mode of actionNakao, Toshifumi; Banba, ShinichiBioorganic & Medicinal Chemistry (2016), 24 (3), 372-377CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A review. Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil. It has been proposed that the site of action for desmethyl-broflanilide is close to G336 in the M3 region of the Drosophila RDL GABA receptor. However, although the site of action for desmethyl-broflanilide appears to overlap with that of macrocyclic lactones, different modes of actions have been demonstrated for desmethyl-broflanilide and the macrocyclic lactones. The mechanisms underlying the high selectivity of meta-diamides are also discussed in this review. Broflanilide is expected to become a prominent insecticide because it is effective against pests with resistance to cyclodienes and fipronil.
- 40Swaminathan, S.; Siddiqui, A. U.; Pinkerton, F. D.; Gerst, N.; Wilson, W. K.; Schroepfer, G. J. Inhibitors of sterol synthesis: 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholestan-15-one, an analog of a potent hypocholesterolemic agent in which its major metabolism is blocked. Biochem. Biophys. Res. Commun. 1994, 201, 168– 173, DOI: 10.1006/bbrc.1994.1684
- 41Lepri, S.; Goracci, L.; Valeri, A.; Cruciani, G. Metabolism study and biological evaluation of bosentan derivatives. Eur. J. Med. Chem. 2016, 121, 658– 670, DOI: 10.1016/j.ejmech.2016.06.006[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVWltL%252FO&md5=c434e8c19b0dcb90af6ba73696388b0bMetabolism study and biological evaluation of bosentan derivativesLepri, Susan; Goracci, Laura; Valeri, Aurora; Cruciani, GabrieleEuropean Journal of Medicinal Chemistry (2016), 121 (), 658-670CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P 450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogs are often designed to block the major sites of metab. In this paper bosentan analogs were synthesized, and their metab. and biol. activity were evaluated. All synthesized compds. showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
- 42(a) Thangavelu, B.; Bhansali, P.; Viola, R. E. Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors. Bioorg. Med. Chem. 2015, 23, 6622– 6631, DOI: 10.1016/j.bmc.2015.09.017 .(b) Thangavelu, B.; Mutthamsetty, V.; Wang, Q.; Viola, R. E. Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease. Bioorg. Med. Chem. 2017, 25, 870– 885, DOI: 10.1016/j.bmc.2016.11.060[Crossref], [PubMed], [CAS], Google Scholar42bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFWlsb%252FJ&md5=a22f8d86c7e49d155bfcf87ddc3cdf85Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan diseaseThangavelu, Bharani; Mutthamsetty, Vinay; Wang, Qinzhe; Viola, Ronald E.Bioorganic & Medicinal Chemistry (2017), 25 (3), 870-885CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Canavan disease is a fatal neurol. disorder caused by defects in the metab. of N-acetyl-L-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA obsd. in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-assocd. enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examd. (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and sol. form of ANAT the authors can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compd. libraries. Two core structures of these moderate binding compds. have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition consts. (Ki values) against ANAT. Slowing the prodn. of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
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- 44(a) Rose, T. E.; Morisseau, C.; Liu, J.-Y.; Inceoglu, B.; Jones, P. D.; Sanborn, J. R.; Hammock, B. D. 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain. J. Med. Chem. 2010, 53, 7067– 7075, DOI: 10.1021/jm100691c[ACS Full Text.
], [CAS], Google Scholar44ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWlsb%252FL&md5=bc2b151553d732942c1ac7e2e963d5241-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure-Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory PainRose, Tristan E.; Morisseau, Christophe; Liu, Jun-Yan; Inceoglu, Bora; Jones, Paul D.; Sanborn, James R.; Hammock, Bruce D.Journal of Medicinal Chemistry (2010), 53 (19), 7067-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine sol. epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analog 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea. This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mech. withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.(b) Lee, K. S. S.; Liu, J.-Y.; Wagner, K. M.; Pakhomova, S.; Dong, H.; Morisseau, C.; Fu, S. H.; Yang, J.; Wang, P.; Ulu, A.; Mate, C. A.; Nguyen, L. V.; Hwang, S. H.; Edin, M. L.; Mara, A. A.; Wulff, H.; Newcomer, M. E.; Zeldin, D. C.; Hammock, B. D. Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. J. Med. Chem. 2014, 57, 7016– 7030, DOI: 10.1021/jm500694p[ACS Full Text
], [CAS], Google Scholar44bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Git77K&md5=1f57ad6909389ac8d101fb548b64c2e2Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo EfficacyLee, Kin Sing Stephen; Liu, Jun-Yan; Wagner, Karen M.; Pakhomova, Svetlana; Dong, Hua; Morisseau, Christophe; Fu, Samuel H.; Yang, Jun; Wang, Peng; Ulu, Arzu; Mate, Christina A.; Nguyen, Long V.; Hwang, Sung Hee; Edin, Matthew L.; Mara, Alexandria A.; Wulff, Heike; Newcomer, Marcia E.; Zeldin, Darryl C.; Hammock, Bruce D.Journal of Medicinal Chemistry (2014), 57 (16), 7016-7030CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of sol. epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, the authors describe a series of newly synthesized sEH inhibitors I [R1 = 4-CF3C6H4, 4-CF3OC6H4; (CF3)2CFC6H4, etc.; R2 = MeCO, MeCH2CO, MeCH2CH2CO, etc.] with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better phys. properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans. - 45Atouioual, B.; Hagmann, L.; Jung, P. M. J.; Lamy, E.; Winkler, T. Atropisomerism about a heptafluoroisopropyl to aryl bond in 5-amino-4-heptafluoroisopropyl indazole. Tetrahedron Lett. 2008, 49, 5403– 5404, DOI: 10.1016/j.tetlet.2008.07.006
- 46(a) Dieckhaus, C. M.; Thompson, C. D.; Roller, S. G.; Macdonald, T. L. Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem.-Biol. Interact. 2002, 142, 99– 117, DOI: 10.1016/S0009-2797(02)00057-1[Crossref], [PubMed], [CAS], Google Scholar.46ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotVKrt78%253D&md5=ade528b1c851e1bf204984d1ae9cf957Mechanisms of idiosyncratic drug reactions: the case of FelbamateDieckhaus, Christine M.; Thompson, Charles D.; Roller, Shane G.; MacDonald, Timothy L.Chemico-Biological Interactions (2002), 142 (1-2), 99-117CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)A review. Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence, and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicol. outcome. As the name implies, IDR are unpredictable and often result in the post-marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include Trovafloxacin, Zileuton, Troglitazone, Tolcapone, and Felbamate. To date there exists no pre-clin. model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, the authors have studied the IDR assocd. with a model compd., Felbamate. The studies with Felbamate are consistent with the theory that compds. which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In addn., the data suggest that under normal physiol. conditions glutathione plays a protective role in preventing IDR during Felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clin. studies with Felbamate have been able to demonstrate an assocn. between reactive metabolite formation and a clin. relevant toxicity; however, addnl. research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.(b) Kapetanovic, I. M.; Torchin, C. D.; Strong, J. M.; Yonekawa, W. D.; Lu, C.; Li, A. P.; Dieckhaus, C. M.; Santos, W. L.; Macdonald, T. L.; Sofia, R. D.; Kupferberg, H. J. Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem.-Biol. Interact. 2002, 142, 119– 134, DOI: 10.1016/S0009-2797(02)00058-3[Crossref], [PubMed], [CAS], Google Scholar.46bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotVKrt7w%253D&md5=ca2ca0812084df77f02f42807c9a5372Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitroKapetanovic, Izet M.; Torchin, Cynthia D.; Strong, John M.; Yonekawa, Wayne D.; Lu, Chuang; Li, Albert P.; Dieckhaus, Christine M.; Santos, Webster L.; MacDonald, Timothy L.; Sofia, R. Duane; Kupferberg, Harvey J.Chemico-Biological Interactions (2002), 142 (1-2), 119-134CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia assocd. with its use. It was proposed that a bioactivation of FBM leading to formation of α,β-unsatd. aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities assocd. with the parent drug. Other members of this class of compds., acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examd. effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metab. and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metab. of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concns. of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as obsd. with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metab. and/or metab. of other endogenous or exogenous compds. and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with crit. cellular macromols. or indirect interference with cellular detoxification mechanisms.(c) Popović, M.; Nierkens, S.; Pieters, R.; Uetrecht, J. Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem. Res. Toxicol. 2004, 17, 1568– 1576, DOI: 10.1021/tx0498197
- 47Parker, R. J.; Hartman, N. R.; Roecklein, B. A.; Mortko, H.; Kupferberg, H. J.; Stables, J.; Strong, J. M. Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by post-mitochondrial suspensions. Chem. Res. Toxicol. 2005, 18, 1842– 1848, DOI: 10.1021/tx050130r
- 48(a) Kupferberg, H. J.; Macdonald, T. L.; Dieckhaus, C. M.; Perhach, J. L.; Sofia, R. D. Fluorofelbamate: pharmacodynamic and metabolic profile of a potent anticonvulsant. Epilepsia 2000, 41 (Suppl 7), 214.(b) Mazarati, A. M.; Sofia, R. D.; Wasterlain, C. G. Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus. Seizure 2002, 11, 423– 430, DOI: 10.1053/seiz.2002.0677[Crossref], [PubMed], [CAS], Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38vnsFyhsQ%253D%253D&md5=95ecc59ab7d7bc7f320d1fb18c53f678Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticusMazarati Andrey M; Sofia R Duane; Wasterlain Claude GSeizure (2002), 11 (7), 423-30 ISSN:1059-1311.PURPOSE: To examine the seizure-protective properties of fluorofelbamate, a felbamate analog, on acute and chronic seizures in an experimental model of self-sustaining status epilepticus (SSSE). METHODS: SSSE was induced by stimulation of the perforant path for 30 min (PPS) through chronically implanted electrodes in free-running adult male Wistar rats. Fluorofelbamate was injected intravenously (i.v.) either 10 min, or 40 min after SSSE induction. Seizure and spike profiles were analyzed off-line. RESULTS: Fluorofelbamate injected during the early stages of SSSE (10 min after the end of PPS), shortened the duration of seizures in a dose-dependent manner. While a dose of 50 mg kg(-1) was ineffective, 100 and 200 mg kg(-1) reduced cumulative seizure time from 393 +/- 10 min to 15 +/- 8 min and 2.4 +/- 0.5 min respectively. Administration of fluorofelbamate (200 and 300 mg kg (-1)) at a late stage of SSSE, which is refractory to treatment with conventional anticonvulsants, also significantly attenuated seizures. Acute fluorofelbamate treatment (200 mg kg(-1) 10 min after PPS) significantly decreased the frequency of spontaneous seizures which follow SSSE after a 'latent' interval. Moreover, in contrast to control animals, fluorofelbamate-treated rats showed regression of spontaneous seizures, and an apparent remission of epilepsy within 2 months after SSSE. CONCLUSIONS: Acute treatment of SSSE with fluorofelbamate showed strong anticonvulsant effects even during the late stages of SSSE. In this model, it also displayed antiepileptogenic properties: it reduced the severity of chronic epilepsy after SSSE and lead to apparent remissions of that epilepsy.
- 49(a) Roecklein, B. A.; Sacks, H. J.; Mortko, H.; Stables, J. Fluorofelbamate. Neurotherapeutics 2007, 4, 97– 101, DOI: 10.1016/j.nurt.2006.11.015[Crossref], [PubMed], [CAS], Google Scholar.49ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXisFaksLk%253D&md5=24365b8c44f2be9837ac64ede8dca327Fluoro0felbamateRoecklein, Bryan A.; Sacks, Harry J.; Mortko, Henry; Stables, JamesNeurotherapeutics (2007), 4 (1), 97-101CODEN: NEURNV; ISSN:1933-7213. (Elsevier)A review. The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clin. studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was obsd. after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (Med-Pointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metab. that has demonstrated, in vitro, to avoid the prodn. of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.(b) Bialer, M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin. Invest. Drugs 2006, 15, 637– 647, DOI: 10.1517/13543784.15.6.637
- 50Xu, S.; Zhu, B.; Teffera, Y.; Pan, D. E.; Caldwell, C. G.; Doss, G.; Stearns, R. A.; Evans, D. C.; Beconi, M. G. Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes. Drug Metab. Dispos. 2005, 33, 121– 130, DOI: 10.1124/dmd.104.001842[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltlensg%253D%253D&md5=2422da6be675647a96f6b76ab1e88a84Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomesXu, Shiyao; Zhu, Bing; Teffera, Yohannes; Pan, Deborah E.; Caldwell, Charles G.; Doss, George; Stearns, Ralph A.; Evans, David C.; Beconi, Maria G.Drug Metabolism and Disposition (2005), 33 (1), 121-130CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-{[(4-trifluoromethoxyphenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1-(trans-4-{[(2,4-difluorophenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride (MRL-A and MRL-B), contg. a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compds. to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addn. of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chem. reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping expts. with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidn. and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16α-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, resp.). Herein, the authors describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.
- 51(a) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.; Harper, B.; Park, Y. J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J.K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E. (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2006, 49, 3614– 3627, DOI: 10.1021/jm060015t[ACS Full Text.
], [CAS], Google Scholar51ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslKht7Y%253D&md5=6ebe737acc317676ca1c7e4178d9719f(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide: A selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetesEdmondson, Scott D.; Mastracchio, Anthony; Mathvink, Robert J.; He, Jiafang; Harper, Bart; Park, You-Jung; Beconi, Maria; Di Salvo, Jerry; Eiermann, George J.; He, Huaibing; Leiting, Barbara; Leone, Joseph F.; Levorse, Dorothy A.; Lyons, Kathryn; Patel, Reshma A.; Patel, Sangita B.; Petrov, Aleksandr; Scapin, Giovanna; Shang, Jackie; Roy, Ranabir Sinha; Smith, Aaron; Wu, Joseph K.; Xu, Shiyao; Zhu, Bing; Thornberry, Nancy A.; Weber, Ann E.Journal of Medicinal Chemistry (2006), 49 (12), 3614-3627CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of β-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogs led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide I, a potent, orally active DPP-4 inhibitor (IC50 = 6.3 nM) with excellent selectivity, oral bioavailability in preclin. species, and in vivo efficacy in animal models. Compd. I was selected for further characterization as a potential new treatment for type 2 diabetes.(b) Sharma, R.; Sun, H.; Piotrowski, D. W.; Ryder, T. F.; Doran, S. D.; Dai, H.; Prakash, C. Metabolism, excretion, and pharmacokinetics of (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human. Drug Metab. Dispos. 2012, 40, 2143– 2161, DOI: 10.1124/dmd.112.047316 - 52Tremblay, M.; Bethell, R. C.; Cordingley, M. G.; Deroy, P.; Duan, J.; Duplessis, M.; Edwards, P. J.; Faucher, A. M.; Halmos, T.; James, C. A.; Kuhn, C.; Lacoste, J. E.; Lamorte, L.; LaPlante, S. R.; Malenfant, É.; Minville, J.; Morency, L.; Morin, S.; Rajotte, D.; Salois, P.; Simoneau, B.; Tremblay, S.; Sturino, C. F. Identification of benzofurano-[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2775– 2780, DOI: 10.1016/j.bmcl.2013.02.042
- 53(a) Meyer, A.; Imming, P. Benzylisoquinoline alkaloids from the papaveraceae: the heritage of Johannes Gadamer (1867–1928). J. Nat. Prod. 2011, 74, 2482– 2487, DOI: 10.1021/np2005049 .(b) Sriram, D.; Yogeeswari, P.; Thirumurugan, R.; Ratan Bal, T. R. Camptothecin and its analogues: a review on their chemotherapeutic potential. Nat. Prod. Res. 2005, 19, 393– 412, DOI: 10.1080/14786410412331299005[Crossref], [PubMed], [CAS], Google Scholar.53bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvFajsrY%253D&md5=7149d979a0e7915678cce4ba5ea8aabbCamptothecin and its analogues: a review on their chemotherapeutic potentialSriram, Dharmarajan; Yogeeswari, Perumal; Thirumurugan, Rathinasabapathy; Ratan Bal, TanushreeNatural Product Research (2005), 19 (4), 393-412CODEN: NPRAAT; ISSN:1478-6419. (Taylor & Francis Ltd.)A review. Topoisomerase I (Topo-I) is a major target for anticancer drug discovery and design. As a result, Topo-I inhibitors constitute an important class of the current anticancer drugs. To date, all of the Topo-I inhibitors that have been clin. evaluated are analogs of camptothecin (CPT), an ext. of the Chinese tree Camptotheca acuminata. CPT has shown significant antitumor activity to lung, ovarian, breast, pancreas and stomach cancers. In this article the, phytochem. aspect, and various structural modifications are comprehensively reviewed as in rings A, B, C, D and E. Biol. activity of camptothecin, other than anticancer, reported till the year 2003 has also been discussed.(c) Olsen, L. R.; Grillo, M. P.; Skonberg, C. Constituents in kava extracts potentially involved in hepatotoxicity: a review. Chem. Res. Toxicol. 2011, 24, 992– 1002, DOI: 10.1021/tx100412m[ACS Full Text
], [CAS], Google Scholar53chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVKkt7k%253D&md5=5b363f611377100cf43a4f74d1595d67Constituents in Kava Extracts Potentially Involved in Hepatotoxicity: A ReviewOlsen, Line R.; Grillo, Mark P.; Skonberg, ChristianChemical Research in Toxicology (2011), 24 (7), 992-1002CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. Aq. kava root prepns. have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava exts. in Western countries, where mainly ethanolic or acetonic exts. are used. The mechanism of toxicity has not been established, although several theories have been put forward. The compn. of the major constituents, the kava lactones, varies according to prepn. method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain compn. of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chem. structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones were identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addn. of GSH to kava exts. has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava ext., such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries. - 54Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 67– 84, DOI: 10.2174/1389200003339270[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlt1Whurs%253D&md5=dcafc824c8bcd0080d256d6dd8c50ae7Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidationMurray, MichaelCurrent Drug Metabolism (2000), 1 (1), 67-84CODEN: CDMUBU ISSN:. (Bentham Science Publishers Ltd.)A review with 110 refs. Cytochrome P 450 (CYP) enzymes catalyze the oxidative conversion of drugs and other lipophilic compds. to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidn. by specific CYPs, whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compds. have been widely employed as com. important pesticide synergists and a no. of derivs. are found in oils and spices. MDP compds. are of considerable toxicol. significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivs. produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clin. importance that possess the MDP structural feature, the synthesis and preclin. evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compds. it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chem. mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clin. value of new drugs.
- 55(a) Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; O’Donnell, J. P.; Boer, J.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 2005, 6, 161– 225, DOI: 10.2174/1389200054021799[Crossref], [PubMed], [CAS], Google Scholar.55ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvF2is7k%253D&md5=b16dfc2de97c40a11218ecc3043bed66A comprehensive listing of bioactivation pathways of organic functional groupsKalgutkar, Amit S.; Gardner, Iain; Obach, R. Scott; Shaffer, Christopher L.; Callegari, Ernesto; Henne, Kirk R.; Mutlib, Abdul E.; Dalvie, Deepak K.; Lee, Jae S.; Nakai, Yasuhiro; O'Donnell, John P.; Boer, Jason; Harriman, Shawn P.Current Drug Metabolism (2005), 6 (3), 161-225CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. The occurrence of idiosyncratic adverse drug reactions during late clin. trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiol. of many drug-induced adverse reactions. Therefore, a thorough examn. of the biochem. reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochem. systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compds. based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as exptl. approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.(b) Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 2011, 24, 1345– 1410, DOI: 10.1021/tx200168d[ACS Full Text
], [CAS], Google Scholar55bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXos1Whtbo%253D&md5=632b73f755738e49eb233bc8dca1fbccStructural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United StatesStepan, Antonia F.; Walker, Daniel P.; Bauman, Jonathan; Price, David A.; Baillie, Thomas A.; Kalgutkar, Amit S.; Aleo, Michael D.Chemical Research in Toxicology (2011), 24 (9), 1345-1410CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examd. as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards assocd. with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addn., the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a mol. that contains a structural alert (RM pos. or neg.) a cause for concern. Could the mol. in its parent form exert toxicity. Can a low dose drug candidate truly mitigate metab.-dependent and -independent idiosyncratic toxicity risks. In an effort to address these questions, we have retrospectively examd. 68 drugs (recalled or assocd. with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochem. characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our anal. revealed that a significant proportion (∼78-86%) of drugs assocd. with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these mols. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochem. properties such as mol. wt., lipophilicity, etc. Approx. half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chem. architecture, and many were found to be RM-pos. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely assocd. with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addn., competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-pos. drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our anal. suggests a need for a more integrated screening paradigm for chem. hazard identification in drug discovery. Thus, in addn. to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compd.(s)) for lead compds., effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compd. liabilities. However, the prospective use of such data in compd. selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiol. mechanisms assocd. with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the assocd. "body burden" of the parent drug and its metabolites will remain an overarching goal in drug discovery. - 56Bolton, J. L.; Trush, M. A.; Penning, T. M.; Dryhurst, G.; Monks, T. J. Role of quinones in toxicology. Chem. Res. Toxicol. 2000, 13, 135– 160, DOI: 10.1021/tx9902082[ACS Full Text
], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1aitr4%253D&md5=6a3064ebe344efe5fb0d53736d8f38cfRole of Quinones in ToxicologyBolton, Judy L.; Trush, Michael A.; Penning, Trevor M.; Dryhurst, Glenn; Monks, Terrence J.Chemical Research in Toxicology (2000), 13 (3), 135-160CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review and discussion with 298 refs. Quinones represent a class of toxicol. intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active mols. which can redox cycle with their semiquinone radicals, leading to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Prodn. of ROS can cause severe oxidative stress within cells through the formation of oxidized cellular macromols., including lipids, proteins, and DNA. Formation of oxidatively damaged bases such as 8-oxodeoxyguanosine has been assocd. with aging and carcinogenesis. Furthermore, ROS can activate a no. of signaling pathways, including protein kinase C and RAS. This review explores the varied cytotoxic effects of quinones using specific examples, including quinones produced from benzene, polycyclic arom. hydrocarbons, estrogens, and catecholamines. The evidence strongly suggests that the numerous mechanisms of quinone toxicity (i.e., alkylation vs. oxidative stress) can be correlated with the known pathol. of the parent compd.(s). - 57(a) Hemeryck, A.; De Vriendt, C. A.; Belpaire, F. M. Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction. Drug Metab. Dispos. 2001, 29, 656– 663.(b) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [3H]-paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 1649– 1657, DOI: 10.1021/tx700132x .(c) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289– 293, DOI: 10.1124/dmd.31.3.289[Crossref], [PubMed], [CAS], Google Scholar57chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFKlt7Y%253D&md5=2336fbc058e49e7b530562809c62ba09Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidineBertelsen, Kirk M.; Venkatakrishnan, Karthik; Von Moltke, Lisa L.; Obach, R. Scott; Greenblatt, David J.Drug Metabolism and Disposition (2003), 31 (3), 289-293CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P 450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To det. whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estd. by varying the time of preincubation as well as the concn. of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estn. of both an apparent inactivator concn. required for half-maximal inactivation (KI) and the maximal rate const. of inactivation (KINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approx. 8-fold redn. in the IC50 value (0.34 vs. 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent KINACT value of 0.17 min-1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metab. of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P 450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.
- 58(a) Anzali, S.; Mederski, W. W. K. R.; Osswald, M.; Dorsch, D. 1. Endothelin antagonists: search for surrogates of methylendioxyphenyl by means of a kohonen neural network. Bioorg. Med. Chem. Lett. 1998, 8, 11– 16, DOI: 10.1016/S0960-894X(97)10150-0 .(b) Iyengar, R. R.; Lynch, J. K.; Mulhern, M. M.; Judd, A. S.; Freeman, J. C.; Gao, J.; Souers, A. J.; Zhao, G.; Wodka, D.; Falls, H. D.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.; Swanson, S.; Su, Z.; Martin, R. L.; Leitz, S. T.; Houseman, K. A.; Diaz, G.; Collins, C. A.; Sham, H. L.; Kym, P. R. An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2007, 17, 874– 878, DOI: 10.1016/j.bmcl.2006.11.065 .(c) Bardelle, C.; Barlaam, B.; Brooks, N.; Coleman, T.; Cross, D.; Ducray, R.; Green, I.; Lambert-van der Brempt, C.; Olivier, A.; Read, J. Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 6242– 6245, DOI: 10.1016/j.bmcl.2010.08.100 .(d) Orr, S. T. M.; Ripp, S. L.; Ballard, T. E.; Henderson, J. L.; Scott, D. O.; Obach, R. S.; Sun, H.; Kalgutkar, A. S. Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure–activity relationships and discovery strategies to mitigate drug–drug interaction risks. J. Med. Chem. 2012, 55, 4896– 4933, DOI: 10.1021/jm300065h[ACS Full Text.
], [CAS], Google Scholar58dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wlur8%253D&md5=aa4aa4f633b3b4f73b3d79917327b0deMechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure-Activity Relationships and Discovery Strategies To Mitigate Drug-Drug Interaction RisksOrr, Suvi T. M.; Ripp, Sharon L.; Ballard, T. Eric; Henderson, Jaclyn L.; Scott, Dennis O.; Obach, R. Scott; Sun, Hao; Kalgutkar, Amit S.Journal of Medicinal Chemistry (2012), 55 (11), 4896-4933CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The importance of mitigating drug-drug interaction (DDI) risks, which arise from inhibition of major human cytochrome P 450 enzymes is a well-established component of the lead optimization process in drug discovery. More recently, there has been much interest in clin. DDIs potentially arising via time- and concn.-dependent cytochrome P 450 inhibition, a phenomenon consistent with mechanism-based inactivation. Inactivated P 450 is catalytically incompetent and must be replenished by newly synthesized protein. Consequently, time-dependent inhibition of P450s presents a greater safety concern compared to reversible inhibition because of the increased propensity for pharmacokinetic interactions upon multiple dosing and the sustained duration of these interactions after discontinuation of the mechanism-based inactivator. Mechanism-based or time-dependent P 450 inhibitors pose an addnl. risk of idiosyncratic drug toxicity since the mechanism of time-dependency often involves the formation of reactive metabolites, which can react with proteins other than the P 450 isoenzyme responsible for catalysis. in vitro time-dependent inhibition (TDI) of P 450 enzymes is now routinely assessed as part of lead optimization efforts in preclin. drug discovery. However, identification of an in vitro TDI liability can raise several questions such as: What is the mechanism of TDI. Does it involve the formation of reactive metabolites. Is there a 1:1 correlation between P 450 TDI and RM formation (as measured from reactive metabolite trapping studies). What is the likelihood that a P 450 time-dependent inhibitor will also cause toxicity. What are the DDI risk mitigation options when dealing with P 450 inactivators in drug discovery - compd. progression or termination. Several drugs exhibit in vitro TDI of P 450 enzymes, but only a fraction thereof causes clin. DDIs. Hence, when do we initiate labor-intensive medicinal chem. efforts to design compds. devoid of P 450 TDI liability. What are the best methods to precisely predict the likelihood of occurrence of clin. DDIs with drug candidates that inactivate P 450 enzymes. What are (if any) the qualifying considerations for clin. progression of a P 450 time-dependent inactivator with projected clin. DDI risks. In an effort to address these questions and hopefully provide answers to some of them, we embarked on the present venture wherein we highlight the current state-of-the-art knowledge in this field with a special emphasis on (a) available biochem. and mechanistic approaches in drug discovery to examine TDI of P 450 isoenzymes with new chem. entities, (b) structure-activity relationship studies with marketed drugs assocd. with DDIs via P 450 inactivation, (c) case studies of medicinal chem. tactics to abrogate P 450 inactivation liability, (d) strategies for progression of P 450 TDI-pos. drug candidates, and (e) the utility of in silico methodol., including the use of physiol.-based pharmacokinetic simulators, in drug discovery to predict the magnitude of clin. DDIs risks anticipated with new clin. candidates.(e) Crawford, J. J.; Kenny, P. W.; Bowyer, J.; Cook, C. R.; Finlayson, J. E.; Heyes, C.; Highton, A. J.; Hudson, J. A.; Jestel, A.; Krapp, S.; Martin, S.; MacFaul, P. A.; McDermott, B. P.; McGuire, T. M.; Morley, A. D.; Morris, J. J.; Page, K. M.; Rosenbrier Ribeiro, L.; Sawney, H.; Steinbacher, S.; Smith, C.; Dossetter, A. G. Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors. J. Med. Chem. 2012, 55, 8827– 8837, DOI: 10.1021/jm301119s - 59Uttamsingh, V.; Gallegos, R.; Liu, J. F.; Harbeson, S. L.; Bridson, G. W.; Cheng, C.; Wells, D. S.; Graham, P. B.; Zelle, R.; Tung, R. Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine. J. Pharmacol. Exp. Ther. 2015, 354, 43– 54, DOI: 10.1124/jpet.115.223768[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFalsLrN&md5=8e7fa68ba7ab319df75badeb50700c20Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetineUttamsingh, Vinita; Gallegos, Richard; Liu, Julie F.; Harbeson, Scott L.; Bridson, Gary W.; Cheng, Changfu; Wells, David S.; Graham, Philip B.; Zelle, Robert; Tung, RogerJournal of Pharmacology and Experimental Therapeutics (2015), 354 (1), 43-54CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Selective deuterium substitution as a means of ameliorating clin. relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium. The new chem. entity, CTP-347 [(3S,4R)-3-((2,2-dideuterobenzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine], demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, as unmodified paroxetine. However, human liver microsomes cleared CTP-347 faster than paroxetine as a result of decreased inactivation of CYP2D6. In phase 1 studies, CTP-347 wasmetabolized more rapidly in humans and exhibited a lower pharmacokinetic accumulation index than paroxetine. These alterations in the metab. profile resulted in significantly reduced drug-drug interactions between CTP-347 and two other CYP2D6-metabolized drugs: tamoxifen (in vitro) and dextromethorphan (in humans). Our results show that precision deuteration can improve the metab. profiles of existing pharmacotherapies without affecting their intrinsic pharmacologies.
- 60(a) Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers, A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh, K. C.; Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2. Bioorg. Med. Chem. Lett. 2004, 14, 4879– 4882, DOI: 10.1016/j.bmcl.2004.07.034 .(b) Nuzzi, A.; Fiasella, A.; Ortega, J. A.; Pagliuca, C.; Ponzano, S.; Pizzirani, D.; Mandrup Bertozzi, S.; Ottonello, G.; Tarozzo, G.; Reggiani, A.; Bandiera, T.; Bertozzi, F.; Piomelli, D. Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies. Eur. J. Med. Chem. 2016, 111, 138– 159, DOI: 10.1016/j.ejmech.2016.01.046[Crossref], [PubMed], [CAS], Google Scholar60bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisVansL4%253D&md5=639c2848d70ba68008db89244c2c8657Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studiesNuzzi, Andrea; Fiasella, Annalisa; Ortega, Jose Antonio; Pagliuca, Chiara; Ponzano, Stefano; Pizzirani, Daniela; Bertozzi, Sine Mandrup; Ottonello, Giuliana; Tarozzo, Glauco; Reggiani, Angelo; Bandiera, Tiziano; Bertozzi, Fabio; Piomelli, DanieleEuropean Journal of Medicinal Chemistry (2016), 111 (), 138-159CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate I is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, the authors describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivs., which have led to the identification of I, and expand these studies to elucidate the principal structural and stereochem. features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of II, a novel inhibitor of human NAAA that shows an improved physicochem. and drug-like profile relative to I. This favorable profile, along with the structural diversity of the carbamic acid chain of I, identify this compd. as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.
- 61(a) Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci, F. C.; Gao, Y.; Moorjani, M.; Connors, P. .J., Jr.; Rowbottom, M. W.; Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders, J.; Reinhart, G.; Chen, T. K.; Killam Bonneville, A. L.; Chen, C. Synthesis and Structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists. J. Med. Chem. 2004, 47, 1259– 1271, DOI: 10.1021/jm030472z .(b) Lynch, J. K.; Freeman, J. C.; Judd, A. S.; Iyengar, R.; Mulhern, M.; Zhao, G.; Napier, J. J.; Wodka, D.; Brodjian, S.; Dayton, B. D.; Falls, D.; Ogiela, C.; Reilly, R. M.; Campbell, T. J.; Polakowski, J. S.; Hernandez, L.; Marsh, K. C.; Shapiro, R.; Knourek-Segel, V.; Droz, B.; Bush, E.; Brune, M.; Preusser, L. C.; Fryer, R. M.; Reinhart, G. A.; Houseman, K.; Diaz, G.; Mikhail, A.; Limberis, J. T.; Sham, H. L.; Collins, C. A.; Kym, P. R. Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety. J. Med. Chem. 2006, 49, 6569– 6584, DOI: 10.1021/jm060683e
- 62Malamas, M. S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A. J. Aminoimidazoles as potent and selective human β-secretase (BACE1) inhibitors. J. Med. Chem. 2009, 52, 6314– 6323, DOI: 10.1021/jm9006752
- 63Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 73– 85, DOI: 10.1007/s00280-005-0128-y[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslGjsbg%253D&md5=97ecbd7d19b5e051255c5c0dc03b215aNovel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterizationRose, William C.; Marathe, Punit H.; Jang, Graham R.; Monticello, Thomas M.; Balasubramanian, Balu N.; Long, Byron; Fairchild, Craig R.; Wall, Monroe E.; Wani, Mansukh C.Cancer Chemotherapy and Pharmacology (2006), 58 (1), 73-85CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacol., toxicol., metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compds. for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclin. antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicol. assessment of GI injury in mice. The generation of parent compd. from BMS-422461 was qual. similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equil. was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclin. GI toxicity, make this novel camptothecin analog attractive for clin. development.
- 64Trachsel, D.; Hadorn, M.; Baumberger, F. Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives. Chem. Biodivers. 2009, 6, 2115– 2135
- 65(a) Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.; Burton, B.; Stack, J. H.; Straley, K. S.; Decker, C. J.; Miller, M.; McCartney, J.; Olson, E. R.; Wine, J. J.; Frizzell, R. A.; Ashlock, M.; Negulescu, P. A. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 18843– 18848, DOI: 10.1073/pnas.1105787108[Crossref], [PubMed], [CAS], Google Scholar.65ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1WnsL%252FO&md5=26ad0866327fd2f645bcc68e91c87354Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (46), 18843-18848, S18843/1-S18843/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amts. of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small mols. Here we describe the in vitro pharmacol. of VX-809, a CFTR corrector that was advanced into clin. development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approx. 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level assocd. with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR cor. by VX-809 exhibited biochem. and functional characteristics similar to normal CFTR, including biochem. susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.(b) Deeks, E. D. Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs 2016, 76, 1191– 1201, DOI: 10.1007/s40265-016-0611-2[Crossref], [PubMed], [CAS], Google Scholar65bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFOmu7bO&md5=7be2b21495bde10b6ed5eb826e53613fLumacaftor/Ivacaftor: A Review in Cystic FibrosisDeeks, Emma D.Drugs (2016), 76 (12), 1191-1201CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Lumacaftor/ivacaftor (Orkambi) is a fixed-dose tablet contg. a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-wk trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with std. therapy, was assocd. with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory vol. in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clin. meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clin. benefit over a further 72 wk of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clin. practice remains to be detd.
- 66Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 1204– 1208, DOI: 10.1021/acsmedchemlett.5b00353[ACS Full Text
], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGms73P&md5=fc681414ace29f39906fdd62c204114bPreclinical Characterization of the FAAH Inhibitor JNJ-42165279Keith, John M.; Jones, William M.; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A.; Webb, Michael; Karbarz, Mark; Scott, Brian P.; Wilson, Sandy J.; Luo, Lin; Wennerholm, Michelle L.; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R.; Breitenbucher, J. GuyACS Medicinal Chemistry Letters (2015), 6 (12), 1204-1208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The preclin. characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 I is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concns. of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compd. was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good phys., ADME, and PD properties of JNJ-42165279 supported it entering the clin. portfolio. - 67Buissonneaud, D. Y.; van Mourik, T.; O’Hagan, D. A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes. Tetrahedron 2010, 66, 2196– 2202, DOI: 10.1016/j.tet.2010.01.049[Crossref], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXitleiurk%253D&md5=b7d6e3599c8e0b9a6364f55c34f362afA DFT study on the origin of the fluorine gauche effect in substituted fluoroethanesBuissonneaud, David Y.; van Mourik, Tanja; O'Hagan, DavidTetrahedron (2010), 66 (12), 2196-2202CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)DFT derived conformational energy profiles of a series of β-substituted α-fluoroethanes (F-CH2CH2-X) have been explored where the substituent X was varied as NH3+, OCOH, NCO, NO2, NHCHO, F, N3, CH=NH, NCS, CH=C=CH2, CH3, CH=CH2, NC, CN, CHO, and CCH. Comparisons were correlated relative to 1,2-difluoroethane, a compd. which exhibits a well known gauche preference. Only four of the compds. displayed an anti preference, with the large majority preferring a gauche conformation. In particular the influence of steric and electrostatic attraction/repulsion between the fluorine atom and the X-substituent was explored by evaluating rotational energy profiles for all compds. and sep. NBO correlations were evaluated to assess the contribution of hyperconjugation to the minimized gauche and anti conformers. In the event the gauche preference for 1,2-difluoroethane was shown to have an origin due largely to σ(C-H)→σ*(C-F) hyperconjugative interactions, whereas the conformational preference for the remaining structures is rationalized by hyperconjugative as well as steric and electrostatic contributions. The anti preferred compds. 13, 14 and 16 possessed triple bonds and the preference arose due to fluorine/p-orbital repulsion.
- 68(a) Deniau, G.; Slawin, A. M. Z.; Lebl, T.; Chorki, F.; Issberner, J. P.; van Mourik, T.; Heygate, J. M.; Lambert, J. J.; Etherington, L. A.; Sillar, K. T.; O’Hagan, D. Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analogue of the neurotransmitter GABA. ChemBioChem 2007, 8, 2265– 2274, DOI: 10.1002/cbic.200700371[Crossref], [PubMed], [CAS], Google Scholar.68ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltlentbc%253D&md5=9ebd7a5dc80ad3dd9c711572f1304f32Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analog of the neurotransmitter GABADeniau, Gildas; Slawin, Alexandra M. Z.; Lebl, Tomas; Chorki, Fatima; Issberner, Jon P.; van Mourik, Tanja; Heygate, Judith M.; Lambert, Jeremy J.; Etherington, Lori-An; Sillar, Keith T.; O'Hagan, DavidChemBioChem (2007), 8 (18), 2265-2274CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)β-Aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calcns. were carried out in a continuum solvent model (PCM-B3LYP) to est. the preferred conformations of 3F-GABA in aq. soln. NMR coupling consts. were calcd. for each conformer and were then used to simulate the NMR spectra to evaluate the soln. conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABAA receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).(b) Yamamoto, I.; Deniau, G. P.; Gavande, N.; Chebib, M.; Johnston, G. A. R.; O’Hagan, D. Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABAC receptors. Chem. Commun. 2011, 47, 7956– 7958, DOI: 10.1039/c1cc12141c .(c) Clift, M. D.; Ji, H.; Deniau, G. P.; O’Hagan, D.; Silverman, R. B. Enantiomers of 4-amino-3-fluorobutanoic acid as substrates for γ-aminobutyric acid aminotransferase. Conformational probes for GABA binding. Biochemistry 2007, 46, 13819– 13828, DOI: 10.1021/bi701249q[ACS Full Text.
], [CAS], Google Scholar68chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1OhsbrO&md5=40d7bf78aab98245d752399c4f468bf1Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA BindingClift, Michael D.; Ji, Haitao; Deniau, Gildas P.; O'Hagan, David; Silverman, Richard B.Biochemistry (2007), 46 (48), 13819-13828CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)γ-Aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degrdn. of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of α-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)- and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH3+ bonds have a strong preference to align gauche rather than anti to each other, it is concluded that on binding of free 3-F-GABA to GABA-AT the optimal conformation places the C-NH3+ and C-F bonds gauche in the (R)-enantiomer but anti in the (S)-enantiomer. Furthermore, the dynamic binding process and the bioactive conformation of GABA bound to GABA-AT have been inferred on the basis of the different biol. behavior of the two enantiomers of 3-F-GABA when they bind to the enzyme. The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily detd. by other biophys. approaches.(d) Crittenden, D. L.; Chebib, M.; Jordan, M. J. T. A quantitative structure-activity relationship investigation into agonist binding at GABAC receptors. J. Mol. Struct.: THEOCHEM 2005, 755, 81– 89, DOI: 10.1016/j.theochem.2005.07.029[Crossref], [CAS], Google Scholar68dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yjt7nI&md5=7993d476114d34309580bfb8ebd06b1dA quantitative structure-activity relationship investigation into agonist binding at GABAC receptorsCrittenden, Deborah L.; Chebib, Mary; Jordan, Meredith J. T.Journal of Molecular Structure: THEOCHEM (2005), 755 (1-3), 81-89CODEN: THEODJ; ISSN:0166-1280. (Elsevier B.V.)The quant. structure-activity relationship (QSAR) model constructed in this work represents the first quant. investigation into agonist binding at GABAC receptors. This model is based upon the three-dimensional structures of γ-aminobutyric acid (GABA) and 12 other biol. active GABA analogs. These structures are obtained by geometry optimization and conformational exploration at MP2/6-31 + G* within the conductor-like screening solvation model (COSMO). The biol. activity data are obtained from previous two-electrode voltage clamp electrophysiol. studies on recombinant GABAC ρ1 receptors expressed in Xenopus laevis oocytes. A QSAR model to predict GABAC agonist binding is constructed from mol. superposition data, generated by least-squares superposition of the stable aq. phase conformations of GABA and its known biol. active analogs to the bioactive conformation of TACA, the most potent GABAC receptor agonist. A significant relationship is found between the root-mean-squared deviation in at. position for the stable conformer of each GABA analog most closely fitting the template TACA structure and the natural log of the normalized biol. activity (R2 = 0.91, p < 0.0001), On the basis of mol. superposition and QSAR results, a pharmacophore model describing three-dimensional features and key interactions at the GABAC receptor binding site is proposed. As there exists no direct exptl. knowledge of structure of the GABAC binding site, this approach provides a feasible and reliable alternative to gain insight into its three-dimensional structure. - 69(a) Hunter, L.; Jolliffe, K. A.; Jordan, M. J. T.; Jensen, P.; MacQuart, R. B. Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivatives. Chem. - Eur. J. 2011, 17, 2340– 2343, DOI: 10.1002/chem.201003320[Crossref], [PubMed], [CAS], Google Scholar.69ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvVWrurw%253D&md5=267a708d47f0c1d6d0eaf4a7278693b0Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivativesHunter, Luke; Jolliffe, Katrina A.; Jordan, Meredith J. T.; Jensen, Paul; MacQuart, Rene B.Chemistry - A European Journal (2011), 17 (8), 2340-2343, S2340/1-S2340/61CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Synthetic access has been archived to all possible stereoisomers of the α,β-difluoro-γ-amino acid motif. These building blocks can readily be coupled to other amino acids under std. conditions with no detectable epimerization, and the resulting, diastereomeric peptides exhibit different, but predictable, conformational behavior. The α,β-difluoro-γ-amino acid motif described here should be of relevance in the future design of shape-controlled bioactive amino acids and peptides.(b) Yamamoto, I.; Jordan, M. J. T.; Gavande, N.; Doddareddy, M. R.; Chebib, M.; Hunter, L. The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABA C receptor. Chem. Commun. 2012, 48, 829– 831, DOI: 10.1039/C1CC15816C[Crossref], [PubMed], [CAS], Google Scholar69bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ersbnK&md5=f48028676c58c2cfafeef583055a10d6The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABAC receptorYamamoto, Izumi; Jordan, Meredith J. T.; Gavande, Navnath; Doddareddy, Munikumar R.; Chebib, Mary; Hunter, LukeChemical Communications (Cambridge, United Kingdom) (2012), 48 (6), 829-831CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)The conformational behavior and GABA receptor activity of the different stereoisomers of 2,3-difluoro-4-aminobutyric acid are described. Two enantiomeric GABAC-active ligands are identified, one of which is an agonist while the other is an antagonist. The results support an existing QSAR model of the bioactive geometry of GABA at GABAC.
- 70Chia, P. W.; Livesey, M. R.; Slawin, A. M. Z.; Van Mourik, T.; Wyllie, D. J. A.; O’Hagan, D. 3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) stereoisomers as conformational probes for exploring agonist binding at NMDA receptors. Chem. - Eur. J. 2012, 18, 8813– 8819, DOI: 10.1002/chem.201200071[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1amu7k%253D&md5=7cba940c2e8ac7341e18ebd9131d7cb33-Fluoro-N-methyl-L-aspartic acid (3F-NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA ReceptorsChia, Poh Wai; Livesey, Matthew R.; Slawin, Alexandra M. Z.; Mourik, Tanja van; Wyllie, David J. A.; O'Hagan, DavidChemistry - A European Journal (2012), 18 (28), 8813-8819, S8813/1-S8813/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)N-Methyl-L-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C-F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepd. by synthesis in enantiomerically pure forms and (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C-F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C-N+ bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilization, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the mol. conformation of β-fluorinated amino acids and thus probing the active conformations of bioactive compds. at receptors.
- 71Hu, X. G.; Thomas, D. S.; Griffith, R.; Hunter, L. Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A. Angew. Chem., Int. Ed. 2014, 53, 6176– 6179, DOI: 10.1002/anie.201403071[Crossref], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosV2hurg%253D&md5=38d2e98bd5d45c24d9f020857cc87b90Stereoselective fluorination alters the geometry of a cyclic peptide: Exploration of backbone-fluorinated analogues of Unguisin AHu, Xiang-Guo; Thomas, Donald S.; Griffith, Renate; Hunter, LukeAngewandte Chemie, International Edition (2014), 53 (24), 6176-6179CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)New methods for enhancing the efficiency of peptide cyclization, and for fine-tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogs of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogs are found to adopt dramatically different secondary structures, controlled by the fluorine stereochem.
- 72Hodges, J. A.; Raines, R. T. Stereoelectronic effects on collagen stability: the dichotomy of 4-fluoroproline diastereomers. J. Am. Chem. Soc. 2003, 125, 9262– 9263, DOI: 10.1021/ja035881z[ACS Full Text
], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltlCksbo%253D&md5=faf38ab73d864733c8501cd4218f74bdStereoelectronic Effects on Collagen Stability: The Dichotomy of 4-Fluoroproline DiastereomersHodges, Jonathan A.; Raines, Ronald T.Journal of the American Chemical Society (2003), 125 (31), 9262-9263CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Collagen is the most abundant protein in animals. Natural collagen consists of a triple helix of (Xaa-Yaa-Gly)n chains, in which the Xaa and Yaa residues are often L-proline. Here, a (2S,4S)-4-fluoroproline (flp) residue is shown to be greatly stabilizing in the Xaa position (but destabilizing in the Yaa position). In contrast, a (2S,4R)-4-fluoroproline (Flp) residue is shown to be greatly destabilizing in the Xaa position (but stabilizing in the Yaa position). The dichotomous effect of the diastereomers appears to arise from a gauche effect, which alters pyrrolidine ring pucker and hence properly (or improperly) preorganizes main-chain dihedral angles. Thus, the rational use of stereoelectronic effects can enhance the conformational stability of a protein. - 73(a) Jakobsche, C. E.; Choudhary, A.; Miller, S. J.; Raines, R. T. n→π* Interaction and n)(π Pauli repulsion are antagonistic for protein stability. J. Am. Chem. Soc. 2010, 132, 6651– 6653, DOI: 10.1021/ja100931y[ACS Full Text.
], [CAS], Google Scholar73ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFyrsbo%253D&md5=a85d11979744c915d9c0c37756d76225n → π* Interaction and n)(π Pauli Repulsion Are Antagonistic for Protein StabilityJakobsche, Charles E.; Choudhary, Amit; Miller, Scott J.; Raines, Ronald T.Journal of the American Chemical Society (2010), 132 (19), 6651-6653CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)In many common protein secondary structures, such as α-, 310, and polyproline II helixes, an n → π* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (Oi-1) of a peptide bond over the antibonding orbital (π*) of Ci:Oi of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of Oi-1 and the bonding orbital (π) of Ci:Oi. We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n → π* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n → π* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n → π* interaction and emphasizes the quantum-mech. nature of the interaction between adjacent amide carbonyl groups in proteins.(b) Newberry, R. W.; VanVeller, B.; Guzei, I. A.; Raines, R. T. n→π* Interactions of amides and thioamides: implications for protein stability. J. Am. Chem. Soc. 2013, 135, 7843– 7846, DOI: 10.1021/ja4033583[ACS Full Text.
], [CAS], Google Scholar73bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsFarsLY%253D&md5=0650f8f39cc5a3eb4a7d3ec6ae760eb4n→π* Interactions of Amides and Thioamides: Implications for Protein StabilityNewberry, Robert W.; VanVeller, Brett; Guzei, Ilia A.; Raines, Ronald T.Journal of the American Chemical Society (2013), 135 (21), 7843-7846CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Carbonyl-carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining exptl. and computational approaches, we show that relevant amidic carbonyl groups assoc. through an n→π* donor-acceptor interaction with an energy of at least 0.27 kcal/mol. The n→π* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor-acceptor orbital interactions rather than dipole-dipole interactions.(c) Kamer, K. J.; Choudhary, A.; Raines, R. T. Intimate interactions with carbonyl groups: dipole-dipole or n→π*?. J. Org. Chem. 2013, 78, 2099– 2103, DOI: 10.1021/jo302265k[ACS Full Text
], [CAS], Google Scholar73chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12mt7jN&md5=a5d3bdd610f31a274d68099bcdf39210Intimate Interactions with Carbonyl Groups: Dipole-Dipole or n→π*?Kamer, Kimberli J.; Choudhary, Amit; Raines, Ronald T.Journal of Organic Chemistry (2013), 78 (5), 2099-2103CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Amide carbonyl groups in proteins can engage in C-O···C=O and C-X···C=O interactions, where X is a halogen. The putative involvement of four poles suggests that these interactions are primarily dipolar. Our survey of crystal structures with a C-X···C=O contact that is short (i.e., within the sum of the X and C van der Waals radii) revealed no preferred C-X···C=O dihedral angle. Moreover, we found that structures with a short X-···C=O contact display the signatures of an n→π* interaction. We conclude that intimate interactions with carbonyl groups do not require a dipole. - 74Fukushima, H.; Hiratate, A.; Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y.; Yamamoto, K. Synthesis and structure–activity relationships of potent 3- or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. 2004, 12, 6053– 6061, DOI: 10.1016/j.bmc.2004.09.010
- 75Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J. D.; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A.-M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Extended structure–activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J. Med. Chem. 2014, 57, 3053– 3074, DOI: 10.1021/jm500031w[ACS Full Text
], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXktVSjt7Y%253D&md5=c52e7b0f1b7a7b056a74577c262a1d6dExtended Structure-Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)Jansen, Koen; Heirbaut, Leen; Verkerk, Robert; Cheng, Jonathan D.; Joossens, Jurgen; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van der Veken, PieterJournal of Medicinal Chemistry (2014), 57 (7), 3053-3074CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncol. applications. The authors previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, the authors explore in detail the structure-activity relationship around this core scaffold. The authors report extensively optimized compds. that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compds. were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo. - 76Staas, D. D.; Savage, K. L.; Sherman, V. L.; Shimp, H. L.; Lyle, T. A.; Tran, L. O.; Wiscount, C. M.; McMasters, D. R.; Sanderson, P. E. J.; Williams, P. D.; Lucas, B. J., Jr.; Krueger, J. A.; Lewis, S. D.; White, R. B.; Yu, S.; Wong, B. K.; Kochansky, C. J.; Anari, M. R.; Yan, Y.; Vacca, J. P. Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability. Bioorg. Med. Chem. 2006, 14, 6900– 6916, DOI: 10.1016/j.bmc.2006.06.040[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptFSksL8%253D&md5=f59e8094ff012efcea5b4ca0a053f4feDiscovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stabilityStaas, Donnette D.; Savage, Kelly L.; Sherman, Vanessa L.; Shimp, Heidi L.; Lyle, Terry A.; Tran, Lekhanh O.; Wiscount, Catherine M.; McMasters, Daniel R.; Sanderson, Philip E. J.; Williams, Peter D.; Lucas, Bobby J.; Krueger, Julie A.; Lewis, S. Dale; White, Rebecca B.; Yu, Sean; Wong, Bradley K.; Kochansky, Christopher J.; Anari, M. Reza; Yan, Youwei; Vacca, Joseph P.Bioorganic & Medicinal Chemistry (2006), 14 (20), 6900-6916CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Previous reports from our labs. described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compds. for further optimization, we identified sites of metab. and designed analogs with 4-fluoroproline in P2 and cyclopropane-contg. side chains in P3 as an approach to reducing metab. and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs contg. (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compds. and by mol. modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compd. from this work, 41 (I), exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity vs. the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
- 77Chiba, J.; Takayama, G.; Takashi, T.; Yokoyama, M.; Nakayama, A.; Baldwin, J. J.; McDonald, E.; Moriarty, K. J.; Sarko, C. R.; Saionz, K. W.; Swanson, R.; Hussain, Z.; Wong, A.; MachinagA, N. Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists. Bioorg. Med. Chem. 2006, 14, 2725– 2746, DOI: 10.1016/j.bmc.2005.11.058
- 78(a) Wang, Y.; Callejo, R.; Slawin, A. M. Z.; O’Hagan, D. The difluoromethylene (CF2) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groups. Beilstein J. Org. Chem. 2014, 10, 18– 25, DOI: 10.3762/bjoc.10.4[Crossref], [PubMed], [CAS], Google Scholar.78ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtFajsLY%253D&md5=08f75f8b382be17a4a74f268267083d5The difluoromethylene (CF2) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groupsWang, Yi; Callejo, Ricardo; Slawin, Alexandra M. Z.; O'Hagan, DavidBeilstein Journal of Organic Chemistry (2014), 10 (), 18-25, 8 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)The syntheses of palmitic acids and a nonadecane are reported with CF2 groups located 1,3 or 1,4 to each other along the aliph. chain. Specifically 8,8,10,10- and 8,8,11,11-tetrafluorohexadecanoic acids are prepd. as well as the singly modified analog 8,8-difluorohexadecanoic acid. Also 8,8,11,11-tetrafluorononadecane is prepd. as a pure hydrocarbon contg. a 1,4-di-CF2 motif. The modified palmitic acids are characterized by differential scanning calorimetry (DSC) to det. m.ps. and phase behavior relative to palmitic acid (62.5 °C). It emerges that 8,8,11,11-tetrafluorohexadecanoic acid, with the CF2 groups placed 1,4- to each other, has a significantly higher m.p. (89.9 °C) when compared to the other analogs and palmitic acid itself. It is a cryst. compd. and the structure reveals an extended anti-zig-zag chain. Similarly 8,8,11,11-tetrafluorononadecane adopts an extended anti-zig-zag structure. This is rationalized by dipolar relaxation between the two CF2 groups placed 1,4 to each other in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce conformational stability.(b) Tavasli, M.; O’Hagan, D.; Pearson, C.; Petty, M. C. The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acids. Chem. Commun. 2002, 1226– 1227, DOI: 10.1039/b202891c[Crossref], [PubMed], [CAS], Google Scholar78bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjslaltL0%253D&md5=19df1ebbe3a055d98534780d93b3e2d9The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acidsTavasli, Mustafa; O'Hagan, David; Pearson, Christopher; Petty, Michael C.Chemical Communications (Cambridge, United Kingdom) (2002), (11), 1226-1227CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)(±)-Erythro- and (±)-threo- 9,10-difluorostearic acids, which differ only by a stereogenic interconversion of a single C-F bond, have significantly different conformational stabilities.
- 79(a) O’Hagan, D. Organofluorine chemistry: synthesis and conformation of vicinal fluoromethylene motifs. J. Org. Chem. 2012, 77, 3689– 3699, DOI: 10.1021/jo300044q[ACS Full Text.
], [CAS], Google Scholar79ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wltbg%253D&md5=fdc040b0921c21fe3c539031e2f6c624Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene MotifsO'Hagan, DavidJournal of Organic Chemistry (2012), 77 (8), 3689-3699CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A review. The C-F bond is the most polar bond in org. chem., and thus the bond has a relatively large dipole moment with a significant -ve charge d. on the fluorine atom and correspondingly a +ve charge d. on carbon. The electrostatic nature of the bond renders it the strongest one in org. chem. However, the fluorine atom itself is nonpolarizable, and thus, despite the charge localization on fluorine, it is a poor hydrogen-bonding acceptor. These properties of the C-F bond make it attractive in the design of nonviscous but polar org. compds., with a polarity limited to influencing the intramol. nature of the mol. and less so intermol. interactions with the immediate environment. In this perspective, the synthesis of aliph. chains carrying multivicinal fluoromethylene motifs is described. It emerges that the dipoles of adjacent C-F bonds orientate relative to each other, and thus, individual diastereoisomers display different backbone carbon chain conformations. These conformational preferences recognize the influence of the well-known gauche effect assocd. with 1,2-difluoroethane but extend to considering 1,3-fluorine-fluorine dipolar repulsions. The synthesis of carbon chains carrying two, three, four, five, and six vicinal fluoromethylene motifs is described, with an emphasis on the research done by the authors. These motifs obey almost predictable conformational behavior, and they emerge as candidates for inclusion in the design of performance org. mols.(b) Wu, D.; Tian, A.; Sun, H. Conformational properties of 1,3-difluoropropane. J. Phys. Chem. A 1998, 102, 9901– 9905, DOI: 10.1021/jp982164w[ACS Full Text.
], [CAS], Google Scholar79bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFKnt7Y%253D&md5=f44c4fc0316ebf223dc223162a793c04Conformational properties of 1,3-difluoropropaneWu, D.; Tian, A.; Sun, H.Journal of Physical Chemistry A (1998), 102 (48), 9901-9905CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The conformational energy order of F(CH2)3F (I) is identified as GG < AG < AA < GG' at various ab initio calcn. levels. This result is analyzed on the basis of the mol. structures, partial charge distributions, and a mol.-mechanics calcn. A strong dipole-dipole interaction between the highly polarized C-F bonds is the decisive factor detg. the conformational-energy preference between 2 gauche-gauche conformers (GG and GG'). This observation suggests that, in addn. to the gauche effect, the intramol. electrostatic interaction should be considered for studying conformational behaviors of mols. with highly polarized bonds in general. The conformational energies obtained in this work challenge earlier interpretations of exptl. data for I.(c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. Angew. Chem., Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.200901956[Crossref], [CAS], Google Scholar79chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFSqtb0%253D&md5=76c049e74a5ebf68bbc4800eb2a82afcSynthesis and Structure of Stereoisomeric Multivicinal HexafluoroalkanesHunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, DavidAngewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored. - 80Scheidt, F.; Selter, P.; Santschi, N.; Holland, M. C.; Dudenko, D. V.; Daniliuc, C.; Mück-Lichtenfeld, C.; Hansen, M. R.; Gilmour, R. Emulating natural product conformation by cooperative, non-covalent fluorine interactions. Chem. - Eur. J. 2017, 23, 6142– 6149, DOI: 10.1002/chem.201604632[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFGqsLfF&md5=2add1cdf79a83f23744d3aef82b8e7ecEmulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine InteractionsScheidt, Felix; Selter, Philipp; Santschi, Nico; Holland, Mareike C.; Dudenko, Dmytro V.; Daniliuc, Constantin; Mueck-Lichtenfeld, Christian; Hansen, Michael Ryan; Gilmour, RyanChemistry - A European Journal (2017), 23 (25), 6142-6149CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Pervasive in Nature, the propane unit is an essential component of numerous bioactive mols. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclization via cyclic ether formation ensures a highly pre-organized structure, while linear scaffolds display more dynamic conformational behavior resulting from rotation about the two internal C(sp3)-C(sp3) bonds. In this study, the replacement of -[CH2]- units by -[CHF]- centers is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviors: These are encoded by the relative configuration of each center. By exploiting cooperative neighboring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theor., crystallog. and spectroscopic analyses. In view of the favorable physicochem. properties assocd. with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.
- 81Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455[ACS Full Text
], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsrzM&md5=20d7a36b75501c02570744857c82f325Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug DiscoveryHuchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, KlausJournal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences. - 82Yokokawa, F.; Wang, G.; Chan, W. L.; Ang, S. H.; Wong, J.; Ma, I.; Rao, S. P. S.; Manjunatha, U.; Lakshminarayana, S. B.; Herve, M.; Kounde, C.; Tan, B. H.; Thayalan, P.; Ng, S. H.; Nanjundappa, M.; Ravindran, S.; Gee, P.; Tan, M.; Wei, L.; Goh, A.; Chen, P.-Y.; Lee, K. S.; Zhong, C.; Wagner, T.; Dix, I.; Chatterjee, A. K.; Pethe, K.; Kuhen, K.; Glynne, R.; Smith, P.; Bifani, P.; Jiricek, J. Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. ACS Med. Chem. Lett. 2013, 4, 451– 455, DOI: 10.1021/ml400071a[ACS Full Text
], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVCltb0%253D&md5=d4a33e9a3fc688dacdb3aa2e8c1c7465Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular AgentsYokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Dick, Thomas; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, JanACS Medicinal Chemistry Letters (2013), 4 (5), 451-455CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Nonracemic (aryl)(fluoroalkyl)tetrahydropyrazolo[1,5-a]pyrimidinecarboxamides I [R = 4-MeC6H4, 5-Me-2-pyridinyl, 5-methyl-2-furyl, 4-(4-morpholinyl)C6H4, 4-(MeOCH2CH2O)C6H4, 4-(3-oxetanyloxy)C6H4; R1 = F3C, F2HC; R2 = 4-FC6H4CH2, 6-MeO-3-pyridinylmethyl, 5-F-2-pyridinylmethyl] were prepd. stereoselectively as potential antitubercular agents; their inhibition of Mycobacterium tuberculosis (Mtb), their aq. solubilities, their plasma protein binding, and their lipophilicities were detd. I were prepd. from aryl Me ketones, Et trifluoro- or difluoroacetate, and Et 3-amino-4-pyrazolecarboxylate; resoln. of the intermediate cis-aryl(fluoroalkyl)tetrahydropyrazolopyrimidinecarboxylic acids by supercrit. fluid chromatog. followed by amidation or aryl modifications yielded the desired products. While I inhibited Mtb with MIC of 0.13-52.2 μM, ent-I did not inhibit Mtb (MIC > 20 μM). In particular, I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) showed a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse antitubercular efficacy model, achieving a redn. of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB. The structure of a nonracemic (methylpyridinyl)(trifluoromethyl)tetrahydropyrazolopyrimidinecarboxylic acid intermediate and its abs. configuration were detd. by X-ray crystallog. - 83Koerts, J.; Soffers, A. E. M. F.; Vervoort, J.; De Jager, A.; Rietjens, I. M. C. M. Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes. Chem. Res. Toxicol. 1998, 11, 503– 512, DOI: 10.1021/tx980053i[ACS Full Text
], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1Giurc%253D&md5=64178da1e0f25584e5aa883b57d3498cOccurrence of the NIH Shift upon the Cytochrome P450-Catalyzed in Vivo and in Vitro Aromatic Ring Hydroxylation of FluorobenzenesKoerts, Janneke; Soffers, Ans E. M. F.; Vervoort, Jacques; De Jager, Adrie; Rietjens, Ivonne M. C. M.Chemical Research in Toxicology (1998), 11 (5), 503-512CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The in vivo cytochrome P 450-catalyzed arom. hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metab. of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro expts. showed a significant amt. of NIH-shifted metabolites for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of addnl. expts. presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metab. of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated benzenes. - 84(a) Shih, I.-h.; Vliegen, I.; Peng, B.; Yang, H.; Hebner, C.; Paeshuyse, J.; Purstinger, G.; Fenaux, M.; Tian, Y.; Mabery, E.; Qi, X.; Bahador, G.; Paulson, M.; Lehman, L. S.; Bondy, S.; Tse, W.; Reiser, H.; Lee, W. A.; Schmitz, U.; Neyts, J.; Zhong, W. Mechanistic characterization of GS-9190 (tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase. Antimicrob. Agents Chemother. 2011, 55, 4196– 4203, DOI: 10.1128/AAC.00307-11 .(b) Hebner, C. M.; Han, B.; Brendza, K. M.; Nash, M.; Sulfab, M.; Tian, Y.; Hung, M.; Fung, W.; Vivian, R. W.; Trenkle, J.; Taylor, J.; Bjornson, K.; Bondy, S.; Liu, X.; Link, J.; Neyts, J.; Sakowicz, R.; Zhong, W.; Tang, H.; Schmitz, U. The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. PLoS One 2012, 7, e39163, DOI: 10.1371/journal.pone.0039163[Crossref], [PubMed], [CAS], Google Scholar.84bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovF2jtro%253D&md5=55998f37569ff6b657425bf95a0b677dThe HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase functionHebner, Christy M.; Han, Bin; Brendza, Katherine M.; Nash, Michelle; Sulfab, Maisoun; Tian, Yang; Hung, Magdeleine; Fung, Wanchi; Vivian, Randall W.; Trenkle, James; Taylor, James; Bjornson, Kyla; Bondy, Steven; Liu, Xiaohong; Link, John; Neyts, Johan; Sakowicz, Roman; Zhong, Weidong; Tang, Hengli; Schmitz, UliPLoS One (2012), 7 (6), e39163CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymic activity in biochem. assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chem. activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further anal. reveals that the aberrantly migrating NS5B species contains the inhibitor mol. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore anal. of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP-mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI) of the viral polymerase.(c) Leivers, M.; Miller, J. F.; Chan, S. A.; Lauchli, R.; Liehr, S.; Mo, W.; Ton, T.; Turner, E. M.; Youngman, M.; Falls, J. G.; Long, S.; Mathis, A.; Walker, J. Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism. J. Med. Chem. 2014, 57, 1964– 1975, DOI: 10.1021/jm401337x .(d) Powers, J. P.; Piper, D. E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J. M.; Jaen, J. C.; Lee, G.; Liu, J.; Peterson, M. G.; Tonn, G. R.; Ye, Q.; Walker, N. P. C.; Wang, Z. SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J. Med. Chem. 2006, 49, 1034– 1046, DOI: 10.1021/jm050859x[ACS Full Text
], [CAS], Google Scholar84dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XksV2ltA%253D%253D&md5=722ac0edb5dabb720e30475ef5925d5fSAR and Mode of Action of Novel Non-Nucleoside Inhibitors of Hepatitis C NS5b RNA PolymerasePowers, Jay P.; Piper, Derek E.; Li, Yang; Mayorga, Veronica; Anzola, John; Chen, James M.; Jaen, Juan C.; Lee, Gary; Liu, Jinqian; Peterson, M. Greg; Tonn, George R.; Ye, Qiuping; Walker, Nigel P. C.; Wang, ZhulunJournal of Medicinal Chemistry (2006), 49 (3), 1034-1046CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochem. potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were detd. by x-ray crystallog., and the inhibitors were found to bind in an allosteric binding site sep. from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compds. in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b. - 85Pinto, D. J.P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 2001, 44, 566– 578, DOI: 10.1021/jm000409z
- 86Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. MedChemComm 2011, 2, 669– 674, DOI: 10.1039/c1md00093d[Crossref], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotl2gt7o%253D&md5=3effbdd29832ac7b57eabbc26c66217bIntramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical spaceAlex, Alexander; Millan, David S.; Perez, Manuel; Wakenhut, Florian; Whitlock, Gavin A.MedChemComm (2011), 2 (7), 669-674CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Utilizing 'beyond rule of five' chem. space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramol. hydrogen bonds in drug mols. is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramol. hydrogen bonding in several 'beyond rule of five' oral drugs is described. Furthermore, the propensity for these drugs to form intramol. hydrogen bonds could be predicted for through modeling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramol. hydrogen bonding in these mols. is supported by intrinsic cell permeability and intestinal absorption data in rat and human.
- 87(a) Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of compounds. J. Med. Chem. 2012, 55, 4877– 4895, DOI: 10.1021/jm201136z[ACS Full Text.
], [CAS], Google Scholar87ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsFKlt7s%253D&md5=6c5dffbb11db6fa893ff3c50fe7778ccStructural Modifications that Alter the P-Glycoprotein Efflux Properties of CompoundsHitchcock, Stephen A.Journal of Medicinal Chemistry (2012), 55 (11), 4877-4895CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This perspective is focused on structural modifications and strategies that can be applied during compd. optimization in order to modulate the P-glycoprotein efflux properties of small mols. with a particular emphasis on implications for CNS penetration. The precise mol. interactions that confer P-glycoprotein efflux remain relatively poorly defined. The promiscuous nature of P-glycoprotein efflux renders the rational circumvention of efflux, while simultaneously optimizing compds. for eficacy, safety, and pharmacokinetic properties, an extremely challenging undertaking.(b) Desai, P. V.; Raub, T. J.; Blanco, M. J. How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg. Med. Chem. Lett. 2012, 22, 6540– 6548, DOI: 10.1016/j.bmcl.2012.08.059[Crossref], [PubMed], [CAS], Google Scholar87bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVSjsr%252FO&md5=a27f286d4349eec6f76b745b19ccf84fHow hydrogen bonds impact P-glycoprotein transport and permeabilityDesai, Prashant V.; Raub, Thomas J.; Blanco, Maria-JesusBioorganic & Medicinal Chemistry Letters (2012), 22 (21), 6540-6548CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. The requirement to cross a biol. membrane can be a complex process esp. if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramol. H-bonds to increase membrane permeability and/or decrease P-gp efflux. - 88(a) Dalvit, C.; Vulpetti, A. Intermolecular and intramolecular hydrogen bonds involving fluorine atoms: implications for recognition, selectivity, and chemical properties. ChemMedChem 2012, 7, 262– 272, DOI: 10.1002/cmdc.201100483[Crossref], [PubMed], [CAS], Google Scholar.88ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xps1CisA%253D%253D&md5=21efccc023f44ed600725e2a834222aeIntermolecular and Intramolecular Hydrogen Bonds Involving Fluorine Atoms: Implications for Recognition, Selectivity, and Chemical PropertiesDalvit, Claudio; Vulpetti, AnnaChemMedChem (2012), 7 (2), 262-272CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A correlation between 19F NMR isotropic chem. shift and close intermol. F···H-X contacts (with X = N or O) has been identified upon anal. of the X-ray crystal structures of fluorinated mols. listed in the Cambridge Structural Database (CSD). An optimal F···X distance involving primary and shielded secondary fluorine atoms in hydrogen-bond formation along with a correlation between F···H distance and F···H-X angle were also derived from the anal. The hydrogen bonds involving fluorine are relevant, not only for the recognition mechanism and stabilization of a preferred conformation, but also for improvement in the permeability of the mols., as shown with examples taken from a proprietary database. Results of an anal. of the small no. of fluorine-contg. natural products listed in the Protein Data Bank (PDB) appear to strengthen the derived correlation between 19F NMR isotropic chem. shift and interactions involving fluorine (also known as the "rule of shielding") and provides a hypothesis for the recognition mechanism and catalytic activity of specific enzymes. Novel chem. scaffolds, based on the rule of shielding, have been designed for recognizing distinct structural motifs present in proteins. It is envisaged that this approach could find useful applications in drug design for the efficient optimization of chem. fragments or promising compds. by increasing potency and selectivity against the desired biomol. target.(b) Dalvit, C.; Invernizzi, C.; Vulpetti, A. Fluorine as a hydrogen-bond acceptor: experimental evidence and computational calculations. Chem. - Eur. J. 2014, 20, 11058– 11068, DOI: 10.1002/chem.201402858[Crossref], [PubMed], [CAS], Google Scholar88bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyqsb3F&md5=c46aba69b8dcf928f00806b5e51bae54Fluorine as a Hydrogen-Bond Acceptor: Experimental Evidence and Computational CalculationsDalvit, Claudio; Invernizzi, Christian; Vulpetti, AnnaChemistry - A European Journal (2014), 20 (35), 11058-11068CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Hydrogen-bonding interactions play an important role in many chem. and biol. systems. Fluorine acting as a hydrogen-bond acceptor in intermol. and intramol. interactions was the subject of many controversial discussions and there are different opinions about it. Recently, the authors proposed a correlation between the propensity of fluorine to be involved in hydrogen bonds and its 19F NMR chem. shift. The authors now provide addnl. exptl. and computational evidence for this correlation. The strength of hydrogen-bond complexes involving the fluorine moieties CH2F, CHF2, and CF3 was measured and characterized in simple systems by using established and novel NMR methods and compared to the known hydrogen-bond complex formed between acetophenone and p-fluorophenol. Implications of these results for 19F NMR screening are analyzed. Computed values of the mol. electrostatic potential at the different fluorine atoms and the anal. of the electron d. topol. at bond crit. points correlate well with the NMR results.
- 89Weiss, M. M.; Williamson, T.; Babu-Khan, S.; Bartberger, M. D.; Brown, J.; Chen, K.; Cheng, Y.; Citron, M.; Croghan, M. D.; Dineen, T. A.; Esmay, J.; Graceffa, R. F.; Harried, S. S.; Hickman, D.; Hitchcock, S. A.; Horne, D. B.; Huang, H.; Imbeah-Ampiah, R.; Judd, T.; Kaller, M. R.; Kreiman, C. R.; La, D. S.; Li, V.; Lopez, P.; Louie, S.; Monenschein, H.; Nguyen, T. T.; Pennington, L. D.; Rattan, C.; San Miguel, T.; Sickmier, E. A.; Wahl, R. C.; Wen, P. H.; Wood, S.; Xue, Q.; Yang, B. H.; Patel, V. F.; Zhong, W. Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid. J. Med. Chem. 2012, 55, 9009– 9024, DOI: 10.1021/jm300119p
- 90Swahn, B.-M.; Kolmodin, K.; Karlström, S.; von Berg, S.; Söderman, P.; Holenz, J.; Berg, S.; Lindström, J.; Sundström, M.; Turek, D.; Kihlström, J.; Slivo, C.; Andersson, L.; Pyring, D.; Rotticci, D.; Öhberg, L.; Kers, A.; Bogar, K.; von Kieseritzky, F.; Bergh, M.; Olsson, L.-L.; Janson, J.; Eketjäll, S.; Georgievska, B.; Jeppsson, F.; Fälting, J. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J. Med. Chem. 2012, 55, 9346– 9361, DOI: 10.1021/jm3009025[ACS Full Text
], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1OmtL%252FM&md5=da7685d90f56449caa77b6e6393e0a7dDesign and Synthesis of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of β-Amyloid PeptidesSwahn, Britt-Marie; Kolmodin, Karin; Karlstroem, Sofia; von Berg, Stefan; Soederman, Peter; Holenz, Joerg; Berg, Stefan; Lindstroem, Johan; Sundstroem, Marie; Turek, Dominika; Kihlstroem, Jacob; Slivo, Can; Andersson, Lars; Pyring, David; Rotticci, Didier; Oehberg, Liselotte; Kers, Annika; Bogar, Krisztian; Bergh, Margareta; Olsson, Lise-Lotte; Janson, Juliette; Eketjaell, Susanna; Georgievska, Biljana; Jeppsson, Fredrik; Faelting, JohannaJournal of Medicinal Chemistry (2012), 55 (21), 9346-9361CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clin. candidate drug for Alzheimer's disease, (S)-32 (I, AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain redn. of Aβ40, is discussed. Due to the basic nature of these compds., they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 (II) and (R)-41 (III) showing large in vitro margins with BACE1 cell IC50 values of 8.6 and 0.16 nM, resp., and hERG IC50 values of 16 and 2.8 μM, resp. Several compds. were advanced into pharmacodynamic studies and demonstrated significant redn. of β-amyloid peptides in mouse brain following oral dosing. - 91Bell, I. M.; Bednar, R. A.; Fay, J. F.; Gallicchio, S. N.; Hochman, J. H.; McMasters, D. R.; Miller-Stein, C.; Moore, E. L.; Mosser, S. D.; Pudvah, N. T.; Quigley, A. G.; Salvatore, C. A.; Stump, C. A.; Theberge, C. R.; Wong, B. K.; Zartman, C. B.; Zhang, X. F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 6165– 6169, DOI: 10.1016/j.bmcl.2006.09.045[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtF2jsr%252FL&md5=55d47a7297cf5ab82fa7bac62a22d98aIdentification of novel, orally bioavailable spirohydantoin CGRP receptor antagonistsBell, Ian M.; Bednar, Rodney A.; Fay, John F.; Gallicchio, Steven N.; Hochman, Jerome H.; McMasters, Daniel R.; Miller-Stein, Cynthia; Moore, Eric L.; Mosser, Scott D.; Pudvah, Nicole T.; Quigley, Amy G.; Salvatore, Christopher A.; Stump, Craig A.; Theberge, Cory R.; Wong, Bradley K.; Zartman, C. Blair; Zhang, Xu-Fang; Kane, Stefanie A.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.Bioorganic & Medicinal Chemistry Letters (2006), 16 (24), 6165-6169CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)A rapid analog approach to identification of spirohydantoin-based CGRP antagonists provided novel, low mol. wt. leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compd. 12 (I), a potent CGRP receptor antagonist (Ki = 21 nM) with good oral bioavailability in three species.
- 92Koshizawa, T.; Morimoto, T.; Watanabe, G.; Watanabe, T.; Yamasaki, N.; Sawada, Y.; Fukuda, T.; Okuda, A.; Shibuya, K.; Ohgiya, T. Optimization of a novel series of potent and orally bioavailable GPR119 agonists. Bioorg. Med. Chem. Lett. 2017, 27, 3249– 3253, DOI: 10.1016/j.bmcl.2017.06.034[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVGms7zF&md5=e0cf277df0c16ba2c9100f52722f406dOptimization of a novel series of potent and orally bioavailable GPR119 agonistsKoshizawa, Tomoaki; Morimoto, Toshiharu; Watanabe, Gen; Watanabe, Toshiaki; Yamasaki, Nao; Sawada, Yoshikazu; Fukuda, Tomoaki; Okuda, Ayumu; Shibuya, Kimiyuki; Ohgiya, TadaakiBioorganic & Medicinal Chemistry Letters (2017), 27 (15), 3249-3253CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50 = 129 nM) was improved by replacing the intramol. hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compd. 12 (EC50 = 53 nM). Optimized compd. 26, which was identified by the further optimization of 12, exhibited potent activity (EC50 = 42 nM) with improved clearance in liver microsomes and induced a 33% redn. in blood glucose area under the curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice.
- 93Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure. J. Med. Chem. 2008, 51, 4858– 4861, DOI: 10.1021/jm800546t[ACS Full Text
], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVyrsb4%253D&md5=2256020d2b940d4c52fb59c6e51b2343Discovery of (R)-4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): A Potent Antagonist of the Human Calcitonin Gene-Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal ExposureDegnan, Andrew P.; Chaturvedula, Prasad V.; Conway, Charles M.; Cook, Deborah A.; Davis, Carl D.; Denton, Rex; Han, Xiaojun; Macci, Robert; Mathias, Neil R.; Moench, Paul; Pin, Sokhom S.; Ren, Shelly X.; Schartman, Richard; Signor, Laura J.; Thalody, George; Widmann, Kimberly A.; Xu, Cen; Macor, John E.; Dubowchik, Gene M.Journal of Medicinal Chemistry (2008), 51 (16), 4858-4861CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chem. leads suffered from modest potency, significant CYP3A4 inhibition, and poor aq. soly. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a mol. with outstanding potency, a favorable predictive toxicol. profile, and remarkable aq. soly. Compd. 4 has good intranasal bioavailablity in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models. - 94Razgulin, A. V.; Mecozzi, S. Binding properties of aromatic carbon-bound fluorine. J. Med. Chem. 2006, 49, 7902– 7906, DOI: 10.1021/jm0600702
- 95(a) Lewis, R. T.; Blackaby, W. P.; Blackburn, T.; Jennings, A. S. R.; Pike, A.; Wilson, R. A.; Hallett, D. J.; Cook, S. M.; Ferris, P.; Marshall, G. R.; Reynolds, D. S.; Sheppard, W. F. A.; Smith, A. J.; Sohal, B.; Stanley, J.; Tye, S. J.; Wafford, K. A.; Atack, J. R. A pyridazine series of α2/α3 subtype selective GABAA agonists for the treatment of anxiety. J. Med. Chem. 2006, 49, 2600– 2610, DOI: 10.1021/jm051144x .(b) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett, D.; Merchant, K. J.; Thomas, S. R. 8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor. Bioorg. Med. Chem. Lett. 2006, 16, 1518– 1522, DOI: 10.1016/j.bmcl.2005.12.037[Crossref], [PubMed], [CAS], Google Scholar95bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1ynurY%253D&md5=e923a5a430fdc343a64cac7b175a31998-Fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptorHumphries, Alexander C.; Gancia, Emanuela; Gilligan, Myra T.; Goodacre, Simon; Hallett, David; Merchant, Kevin J.; Thomas, Steve R.Bioorganic & Medicinal Chemistry Letters (2006), 16 (6), 1518-1522CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochem. mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochem. mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 2'-fluoro-5'-[8-fluoro-7-(2-hydroxy-2-propyl)imidazo[1,2-a]pyridin-3-yl]biphenyl-2-carbonitrile acts as a bioisosteric replacement for imidazopyrimidine in the GABAA receptor modulator 2'-fluoro-5'-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile.
- 96(a) Robarge, K. D.; Lee, W.; Eigenbrot, C.; Ultsch, M.; Wiesmann, C.; Heald, R.; Price, S.; Hewitt, J.; Jackson, P.; Savy, P.; Burton, B.; Choo, E. F.; Pang, J.; Boggs, J.; Yang, A.; Yang, X.; Baumgardner, M. Structure based design of novel 6,5 heterocbicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a]pyrazine G-479. Bioorg. Med. Chem. Lett. 2014, 24, 4714– 4723, DOI: 10.1016/j.bmcl.2014.08.008
- 97(a) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Yang, X.; Richards, M.; Shipps, G. W., Jr. Discovery of a novel series of CHK1 kinase inhibitors with a distinctive hinge binding mode. ACS Med. Chem. Lett. 2012, 3, 123– 128, DOI: 10.1021/ml200249h[ACS Full Text.
], [CAS], Google Scholar97ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpslGntQ%253D%253D&md5=0033fbe5837cc4c6287c4a5428665247Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding ModeHuang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Yang, Xianshu; Richards, Matthew; Shipps, Gerald W.ACS Medicinal Chemistry Letters (2012), 3 (2), 123-128CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection-mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.(b) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Richards, M.; Tadikonda, P. K.; Reddy, P. A.; Zhao, L.; Siddiqui, M. A.; Parry, D.; Davis, N.; Seghezzi, W.; Wiswell, D.; Shipps, G. W., Jr. Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2590– 2594, DOI: 10.1016/j.bmcl.2013.02.108[Crossref], [PubMed], [CAS], Google Scholar97bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksFars7o%253D&md5=f9288637d69888cf8a808eb72897ba70Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitorsHuang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Richards, Matthew; Tadikonda, Praveen K.; Reddy, Panduranga Adulla; Zhao, Lianyun; Arshad Siddiqui, M.; Parry, David; Davis, Nicole; Seghezzi, Wolfgang; Wiswell, Derek; Shipps, Gerald W.Bioorganic & Medicinal Chemistry Letters (2013), 23 (9), 2590-2594CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)N-(Piperazinylaryl) amino- and heterocyclyl-substituted thiazolecarboxamides such as N-(piperazinylpyridinyl) (oxoisoindolinyl)thiazolecarboxamide I were prepd. as selective inhibitors of checkpoint kinase 1 (CHK1). Both the identities of the amino substituent on the thiazole ring and the aryl ring connecting the piperazine moiety to the thiazolecarboxamide were varied to det. the structure-activity relationship for enzymic and cellular CHK1 inhibition and for selectivity over the related kinase CHK2. I inhibited CHK1 with IC50 values against the enzyme and against cells of 1 nM and 30 nM, resp., with > 104 selectivity for CHK1 over CHK2; the inhibition of CYP 3A4, 2D6, and 2C9 in human liver microsomes, of hERG in various assays, and of other kinases and of various G protein-coupled receptors by I was detd. The structure of a complex of I with CHK1 was detd. by X-ray crystallog.; the topol. of its binding to the ATP-binding site of CHK1 is detd. - 98(a) Koller, A. N.; Božilović, J.; Engels, J. W.; Gohlke, H. Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs. Nucleic Acids Res. 2010, 38, 3133– 3146, DOI: 10.1093/nar/gkp1237[Crossref], [PubMed], [CAS], Google Scholar.98ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFyktbY%253D&md5=c13d7b313f142d43b366fe82f4affa71Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogsKoller, Alrun N.; Bozilovic, Jelena; Engels, Joachim W.; Gohlke, HolgerNucleic Acids Research (2010), 38 (9), 3133-3146CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)The thermodn. of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estd. by potential of mean force calcns. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol-1. Decompg. the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol-1 compared to non-fluorinated analogs. This is attributed to stabilizing C-F...H-N dipolar interactions and stronger N...H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-Methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first exptl. evidence for nitrogen-contg. heterocylces as bioisosteres of arom. rings bearing fluorine atoms.(b) Gohlke, H.; Božilović, J.; Engels, J. W. Synthesis and properties of fluorinated nucleobases in DNA and RNA. Mol. Medicine Med. Chem. 2012, 6, 3– 32, DOI: 10.1142/9781848166363_0001[Crossref], [CAS], Google Scholar98bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1CitbvF&md5=401399b94327a1d01accc6a736983282Synthesis and properties of fluorinated nucleobases in DNA and RNAGohlke, Holger; Bozilovic, Jelena; Engels, Joachim W.Molecular Medicine and Medicinal Chemistry (2012), 6 (Fluorine in Pharmaceutical and Medicinal Chemistry), 3-32CODEN: MMMCCE ISSN:. (Imperial College Press)A review with refs. Synthesis and crystallog. studies of fluorinated non-polar nucleoside isosteres and thermodn. analyses and computer simulations of model DNA and RNAs incorporating them are reviewed.
- 99(a) Giroud, M.; Harder, M.; Kuhn, B.; Haap, W.; Trapp, N.; Schweizer, W. B.; Schirmeister, T.; Diederich, F. Fluorine scan of inhibitors of the cysteine protease human cathepsin L: dipolar and quadrupolar effects in the π-stacking of fluorinated phenyl rings on peptide amide bonds. ChemMedChem 2016, 11, 1042– 1047, DOI: 10.1002/cmdc.201600132[Crossref], [PubMed], [CAS], Google Scholar.99ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtlSit7o%253D&md5=298c19d0abfdee7fa7c9593b21da62f0Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide BondsGiroud, Maude; Harder, Michael; Kuhn, Bernd; Haap, Wolfgang; Trapp, Nils; Schweizer, W. Bernd; Schirmeister, Tanja; Diederich, FrancoisChemMedChem (2016), 11 (10), 1042-1047CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chem. calcns. In the exptl. study, the Ph substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by addnl. interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calcns. strongly support the contributions of the mol. quadrupole moments of the fluorinated Ph rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.(b) Giroud, M.; Ivkovic, J.; Martignoni, M.; Fleuti, M.; Trapp, N.; Haap, W.; Kuglstatter, A.; Benz, J.; Kuhn, B.; Schirmeister, T.; Diederich, F. Inhibition of the cysteine protease human cathepsin L by triazine nitriles: amide···heteroarene π-stacking interactions and chalcogen bonding in the S3 pocket. ChemMedChem 2017, 12, 257– 270, DOI: 10.1002/cmdc.201600563[Crossref], [PubMed], [CAS], Google Scholar99bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlyisw%253D%253D&md5=c8515e2082b8874cfd943b0ff61a6510Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide···Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 PocketGiroud, Maude; Ivkovic, Jakov; Martignoni, Mara; Fleuti, Marianne; Trapp, Nils; Haap, Wolfgang; Kuglstatter, Andreas; Benz, Joerg; Kuhn, Bernd; Schirmeister, Tanja; Diederich, FrancoisChemMedChem (2017), 12 (3), 257-270CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene···peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory consts. (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroarom. ligands feature enhanced binding by comparison with hydrocarbon analogs. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nM) and benzothiazolyl (Ki=17 nM) ligands was enhanced by intermol. C-S···O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
- 100Császár, P.; Császár, A. On the dipole moments of fluorobenzenes by quantum chemical methods. J. Mol. Struct.: THEOCHEM 1984, 110, 405– 407, DOI: 10.1016/0166-1280(84)80090-1
- 101van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.; Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russell, M. G. N.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.; Castro, J. L. Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles. J. Med. Chem. 1999, 42, 2087– 2104, DOI: 10.1021/jm981133m[ACS Full Text
], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnvVymtro%253D&md5=2cc155335a622de308f285e470f7b570Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(1-piperazinyl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profilesvan Niel, Monique B.; Collins, Ian; Beer, Margaret S.; Broughton, Howard B.; Cheng, Susan K. F.; Goodacre, Simon C.; Heald, Anne; Locker, Karen L.; MacLeod, Angus M.; Morrison, Denise; Moyes, Christopher R.; O'Connor, Desmond; Pike, Andrew; Rowley, Michael; Russel, N.; Sohal, Balbinder; Stanton, Josephine A.; Thomas, Steven; Verrier, Hugh; Watt, Alan P.; Castro, Jose L.Journal of Medicinal Chemistry (1999), 42 (12), 2087-2104CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)It has previously been reported that a 3-(3-(1-piperazinyl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal, versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivs. with one or two fluorines in the Pr linker were developed. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compds., and this redn. of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted. - 102(a) Paulini, R.; Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788– 1805, DOI: 10.1002/anie.200462213[Crossref], [CAS], Google Scholar.102ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXislWkt7s%253D&md5=6ad842547313b27fc1676e9c3a001909Orthogonal multipolar interactions in structural chemistry and biologyPaulini, Ralph; Mueller, Klaus; Diederich, FrancoisAngewandte Chemie, International Edition (2005), 44 (12), 1788-1805CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The past few decades of mol. recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biol. receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A no. of illustrative examples of these interactions found in X-ray crystal structures of small mols. and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chem. and biol. mol. recognition processes.(b) Xing, L.; Keefer, C.; Brown, M. F. Fluorine multipolar interaction: towards elucidating its energetics in binding recognition. J. Fluorine Chem. 2017, 198, 47– 53, DOI: 10.1016/j.jfluchem.2016.12.013[Crossref], [CAS], Google Scholar102bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlartg%253D%253D&md5=9dedd4fdc6214090960005fc33375ef2Fluorine multipolar interaction: Toward elucidating its energetics in binding recognitionXing, Li; Keefer, Christopher; Brown, Matthew F.Journal of Fluorine Chemistry (2017), 198 (), 47-53CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)Multipolar interactions have gained attention due to their roles in mol. recognition events of chem. and biol. systems. Structural evidence suggests that the fluorine multipolar interaction is a favorable mol. interaction in the paradigm of protein-ligand recognition. With an aim to understand its propensity and energetics in ligand-protein assembly, the authors mined the "Pfizer protein-ligand x-ray structure database" with three-dimensional constraints for the presence of such interactions. A set of transformation rules were applied to generate their corresponding matched mol. pairs (MMPs) that bear hydrogen(s) in place of the interacting fluorine(s). Biol. activities were retrieved from the authors' internal data warehouse for the MMPs with and without the ability to form the multipolar interaction. On the basis of the obsd. potency differences the authors detd. that the free energy gain assocd. with the fluorine multipolar interaction is relatively modest, ∼0.3-0.6 kcal/mol, and the net impact on lipophilic efficiency (LipE) is essentially neutral. A general guideline for medicinal chemists has emerged from this study, enabling a more rational employment of this type of interaction in mol. design.
- 103(a) Shi, A.; Murai, M. J.; He, S.; Lund, G.; Hartley, T.; Purohit, T.; Reddy, G.; Chruszcz, M.; Grembecka, J.; Cierpicki, T. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 2012, 120, 4461– 4469, DOI: 10.1182/blood-2012-05-429274[Crossref], [PubMed], [CAS], Google Scholar.103ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVWgtb7J&md5=c1ab14816cf5ea3590fe03b0ed405ea5Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemiaShi, Aibin; Murai, Marcelo J.; He, Shihan; Lund, George; Hartley, Thomas; Purohit, Trupta; Reddy, Gireesh; Chruszcz, Maksymilian; Grembecka, Jolanta; Cierpicki, TomaszBlood (2012), 120 (23), 4461-4469CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Menin functions as a crit. oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resoln. crystal structure of human menin in complex with a small-mol. inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compd. binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compd. that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-mol. inhibitor.(b) Pollock, J.; Borkin, D.; Lund, G.; Purohit, T.; Dyguda-Kazimierowicz, E.; Grembecka, J.; Cierpicki, T. Rational design of orthogonal multipolar interactions with fluorine in protein–ligand complexes. J. Med. Chem. 2015, 58, 7465– 7474, DOI: 10.1021/acs.jmedchem.5b00975[ACS Full Text.
], [CAS], Google Scholar103bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOju73F&md5=56d54cdfbf8af7d68666572a57335c51Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand ComplexesPollock, Jonathan; Borkin, Dmitry; Lund, George; Purohit, Trupta; Dyguda-Kazimierowicz, Edyta; Grembecka, Jolanta; Cierpicki, TomaszJournal of Medicinal Chemistry (2015), 58 (18), 7465-7474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Multipolar interactions involving fluorine and the protein backbone have been frequently obsd. in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to the high affinity of small mol. inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogs by systematically changing the no. of fluorine atoms, and we detd. high-resoln. crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin-MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine-backbone interactions in protein-ligand complexes, we developed a computational algorithm named FMAP, which calcs. fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Anal. of the menin-MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine-backbone interactions may represent a particularly attractive approach to improve inhibitors of protein-protein interactions.(c) Grembecka, J.; He, S.; Shi, A.; Purohit, T.; Muntean, A. G.; Sorenson, R. J.; Showalter, H. D.; Murai, M. J.; Belcher, A. M.; Hartley, T.; Hess, J. L.; Cierpicki, T. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 2012, 8, 277– 284, DOI: 10.1038/nchembio.773[Crossref], [PubMed], [CAS], Google Scholar.103chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlOrsrY%253D&md5=55eb9f353031dfef4c1a281b0ac28cbaMenin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemiaGrembecka, Jolanta; He, Shihan; Shi, Aibin; Purohit, Trupta; Muntean, Andrew G.; Sorenson, Roderick J.; Showalter, Hollis D.; Murai, Marcelo J.; Belcher, Amalia M.; Hartley, Thomas; Hess, Jay L.; Cierpicki, TomaszNature Chemical Biology (2012), 8 (3), 277-284CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-mol. inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compds. effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compds. provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.(d) Borkin, D.; Pollock, J.; Kempinska, K.; Purohit, T.; Li, X.; Wen, B.; Zhao, T.; Miao, H.; Shukla, S.; He, M.; Sun, D.; Cierpicki, T.; Grembecka, J. Property focused structure-based optimization of small molecule inhibitors of the protein–protein interaction between menin and mixed lineage leukemia (MLL). J. Med. Chem. 2016, 59, 892– 913, DOI: 10.1021/acs.jmedchem.5b01305[ACS Full Text
], [CAS], Google Scholar103dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XltFersw%253D%253D&md5=f89b6eda72671f133a38181b3b23632dProperty Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)Borkin, Dmitry; Pollock, Jonathan; Kempinska, Katarzyna; Purohit, Trupta; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Miao, Hongzhi; Shukla, Shirish; He, Miao; Sun, Duxin; Cierpicki, Tomasz; Grembecka, JolantaJournal of Medicinal Chemistry (2016), 59 (3), 892-913CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Development of potent small mol. inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compds., which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compd. 1 (MI-136) to identify compds. suitable for in vivo studies in mice. This work resulted in the identification of compd. 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications. - 104(a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.; D’Arcy, A.; Stihle, M.; Müller, K.; Diederich, F. A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F···C═O interactions. Angew. Chem., Int. Ed. 2003, 42, 2507– 2511, DOI: 10.1002/anie.200351268[Crossref], [CAS], Google Scholar.104ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXkvFCrt7k%253D&md5=f9851cb27f3e9d10152ad10abcd5c965A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: Evidence for C-F···C=O interactionsOlsen, Jacob A.; Banner, David W.; Seiler, Paul; Sander, Ulrike Obst; D'Arcy, Allan; Stihle, Martine; Mueller, Klaus; Diederich, FrancoisAngewandte Chemie, International Edition (2003), 42 (22), 2507-2511CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A highly fluorophilic environment comprising the H-Cα-C=O unit of Asn 98 in the active site of thrombin was identified by X-ray crystallog. of a complex formed between the enzyme and a synthetic inhibitor (see partial X-ray structure, distances are in Angstroms). Short C-F···H-Cα and C-F···C=O contacts involving H-Cα-C=O fragments were also frequently obsd. in small-mol. X-ray crystal structures.(b) Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.; Kansy, M.; Müller, K.; Diederich, F. Fluorine interactions at the thrombin active site: protein backbone fragments H-Cα-C═O comprise a favorable C-F environment and interactions of C-F with electrophiles. ChemBioChem 2004, 5, 666– 675, DOI: 10.1002/cbic.200300907[Crossref], [PubMed], [CAS], Google Scholar.104bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFeqtb8%253D&md5=1171f81bb64f9c04f849d3aaa63e5c27Fluorine interactions at the thrombin active site: Protein backbone fragments H-Cα-C=O comprise a favorable C-F environment and interactions of C-F with electrophilesOlsen, Jacob A.; Banner, David W.; Seiler, Paul; Wagner, Bjoern; Tschopp, Thomas; Obst-Sander, Ulrike; Kansy, Manfred; Mueller, Klaus; Diederich, FrancoisChemBioChem (2004), 5 (5), 666-675CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4-fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X-ray crystal-structure anal. of the protein-ligand complex revealed favorable C-F···H-Cα-C=O and C-F···C=O interactions of the 4-F substituent of the inhibitor with the backbone H-Cα-C=O unit of Asn98. The importance of these interactions was further corroborated by the anal. of small-mol. X-ray crystal-structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the C-F···C=O interactions that are obsd. for both arom. and aliph. C-F units and a variety of carbonyl and carboxyl derivs., the F atom approaches the C=O C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions C-F···C≡N, C-F···C-F1 and C-F···NO2, in which the F atoms interact at subvan der Waals distances with the electrophilic centers.(c) Schweizer, E.; Hoffmann-Röder, A.; Olsen, J. A.; Seiler, P.; Obst-Sander, U.; Wagner, B.; Kansy, M.; Banner, D. W.; Diederich, F. Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors. Org. Biomol. Chem. 2006, 4, 2364– 2375, DOI: 10.1039/B602585D
- 105Bauer, M. R.; Jones, R. N.; Baud, M. G. J.; Wilcken, R.; Boeckler, F. M.; Fersht, A. R.; Joerger, A. C.; Spencer, J. Harnessing fluorine-sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs. ACS Chem. Biol. 2016, 11, 2265– 2274, DOI: 10.1021/acschembio.6b00315[ACS Full Text
], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptlOgsbg%253D&md5=73f018ccf7a437efc42ea0cc4eb2843fHarnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue DrugsBauer, Matthias R.; Jones, Rhiannon N.; Baud, Matthias G. J.; Wilcken, Rainer; Boeckler, Frank M.; Fersht, Alan R.; Joerger, Andreas C.; Spencer, JohnACS Chemical Biology (2016), 11 (8), 2265-2274CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-mol. stabilizers of this mutant. One of these mols., PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temp. of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small mol. ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole Et anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol-1 atom-1). High-resoln. crystal structures of the Y220C-ligand complexes combined with quantum chem. calcns. revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells. - 106(a) Lou, Y.; Sweeney, Z. K.; Kuglstatter, A.; Davis, D.; Goldstein, D. M.; Han, X.; Hong, J.; Kocer, B.; Kondru, R. K.; Litman, R.; McIntosh, J.; Sarma, K.; Suh, J.; Taygerly, J.; Owens, T. D. Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s tyrosine kinase (BTK) inhibitor scaffold. Bioorg. Med. Chem. Lett. 2015, 25, 367– 371, DOI: 10.1016/j.bmcl.2014.11.030[Crossref], [PubMed], [CAS], Google Scholar.106ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitValtrvF&md5=e1f4815a0df9e91ce9150eacf196fc07Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffoldLou, Yan; Sweeney, Zachary K.; Kuglstatter, Andreas; Davis, Dana; Goldstein, David M.; Han, Xiaochun; Hong, Junbae; Kocer, Buelent; Kondru, Rama K.; Litman, Renee; McIntosh, Joel; Sarma, Keshab; Suh, Judy; Taygerly, Joshua; Owens, Timothy D.Bioorganic & Medicinal Chemistry Letters (2015), 25 (2), 367-371CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a satd. bicyclic ring system yields no apparent benefit, the same operation on an unsatd. bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent mols. and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.(b) Lou, Y.; Han, X.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth, M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.; Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.; Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D. Structure-based drug design of RN486, a potent and selective Bruton’s tyrosine kinase (BTK) Inhibitor, for the treatment of rheumatoid arthritis. J. Med. Chem. 2015, 58, 512– 516, DOI: 10.1021/jm500305p[ACS Full Text.
], [CAS], Google Scholar106bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsl2qtb8%253D&md5=dc3c069b0e876f44846a30e3aa6a894aStructure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid ArthritisLou, Yan; Han, Xiaochun; Kuglstatter, Andreas; Kondru, Rama K.; Sweeney, Zachary K.; Soth, Michael; McIntosh, Joel; Litman, Renee; Suh, Judy; Kocer, Buelent; Davis, Dana; Park, Jaehyeon; Frauchiger, Sandra; Dewdney, Nolan; Zecic, Hasim; Taygerly, Joshua P.; Sarma, Keshab; Hong, Junbae; Hill, Ronald J.; Gabriel, Tobias; Goldstein, David M.; Owens, Timothy D.Journal of Medicinal Chemistry (2015), 58 (1), 512-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alc. group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compd. I (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclin. characterization based on its favorable properties.(c) Lou, Y.; Lopez, F.; Jiang, Y.; Han, X.; Brotherton, C.; Billedeau, R.; Gabriel, S.; Gleason, S.; Goldstein, D. M.; Hilgenkamp, R.; Kocer, B.; Orzechowski, L.; Tan, J.; Wovkulich, P.; Wen, B.; Fry, D.; Di Lello, P.; Chen, L.; Zhang, F.-j.; Fretland, J.; Nangia, A.; Yang, T.; Owens, T. D. Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK). Bioorg. Med. Chem. Lett. 2017, 27, 632– 635, DOI: 10.1016/j.bmcl.2016.11.092[Crossref], [PubMed], [CAS], Google Scholar106chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFClt7zI&md5=55afd6fa4c4da934dfbe0654aaf5031dMitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK)Lou, Yan; Lopez, Francisco; Jiang, Yongying; Han, Xiaochun; Brotherton, Chris; Billedeau, Roland; Gabriel, Steve; Gleason, Shelly; Goldstein, David M.; Hilgenkamp, Ramona; Kocer, Buelent; Orzechowski, Lucja; Tan, Jenny; Wovkulich, Peter; Wen, Bo; Fry, David; Di Lello, Paola; Chen, Lucy; Zhang, Fang-jie; Fretland, Jennifer; Nangia, Anjali; Yang, Tian; Owens, Timothy D.Bioorganic & Medicinal Chemistry Letters (2017), 27 (3), 632-635CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a no. of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead mols. in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compd. 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation assocn. of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS anal. of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compd. 7 (RN941) with significantly reduced covalent binding of 26 pmol/mg protein. - 107Hao, G.-F.; Wang, F.; Li, H.; Zhu, X.-L.; Yang, W.-C.; Huang, L.-S.; Wu, J.-W.; Berry, E. A.; Yang, G.-F. Computational discovery of picomolar Qo site inhibitors of cytochrome bc1 complex. J. Am. Chem. Soc. 2012, 134, 11168– 11176, DOI: 10.1021/ja3001908[ACS Full Text
], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotlemtLo%253D&md5=23821de7aaecdbcb8aa513a05fd5bc87Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 ComplexHao, Ge-Fei; Wang, Fu; Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A.; Yang, Guang-FuJournal of the American Chemical Society (2012), 134 (27), 11168-11176CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A crit. challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophys. method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compd. 4 (Ki = 881.80 nM, porcine bc1), the most potent compd. 4f displayed 20 507-fold improved binding affinity (Ki = 43.00 pM). Compd. 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Addnl., the crystal structure of compd. 4e (Ki = 83.00 pM) bound to the chicken bc1 was detd. at 2.70 Å resoln., providing a mol. basis for understanding its ultrapotency. To the authors' knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophys. screening techniques. - 108García-LLinás, X.; Bauzá, A.; Seth, S. K.; Frontera, A. Importance of R-CF3•••O tetrel bonding interactions in biological systems. J. Phys. Chem. A 2017, 121, 5371– 5376, DOI: 10.1021/acs.jpca.7b06052
- 109Cisneros, J. A.; Robertson, M. J.; Valhondo, M.; Jorgensen, W. L. Irregularities in enzyme assays: the case of macrophage migration inhibitory factor. Bioorg. Med. Chem. Lett. 2016, 26, 2764– 2767, DOI: 10.1016/j.bmcl.2016.04.074[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFCqtLs%253D&md5=a232a355d251396f4d19e79954bf469bIrregularities in enzyme assays: The case of macrophage migration inhibitory factorCisneros, Jose A.; Robertson, Michael J.; Valhondo, Margarita; Jorgensen, William L.Bioorganic & Medicinal Chemistry Letters (2016), 26 (12), 2764-2767CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhibitors of human macrophage migration inhibitory factor (MIF) previously reported in the literature have been reexamd. by synthesis, assaying for tautomerase activity, and protein crystallog. Substantial inconsistencies between prior and current assay results are noted. They appear to arise from difficulties with the tautomerase substrates, soly. issues, and esp. covalent inhibition. Incubation time variation shows that several compds. are covalent or slow-binding inhibitors. Two protein crystal structures are provided; one confirms that a twice-discovered compd. is a covalent inhibitor.
- 110(a) Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; Yang, H.; Gross, S.; Artin, E.; Saada, V.; Mylonas, E.; Quivoron, C.; Popovici-Muller, J.; Saunders, J. O.; Salituro, F. G.; Yan, S.; Murray, S.; Wei, W.; Gao, Y.; Dang, L.; Dorsch, M.; Agresta, S.; Schenkein, D. P.; Biller, S. A.; Su, S. M.; de Botton, S.; Yen, K. E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013, 340, 622– 626, DOI: 10.1126/science.1234769[Crossref], [PubMed], [CAS], Google Scholar.110ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmslWksbs%253D&md5=fe3db6b043a8b31fb661d0bdbd75e19fTargeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular DifferentiationWang, Fang; Travins, Jeremy; De La Barre, Byron; Penard-Lacronique, Virginie; Schalm, Stefanie; Hansen, Erica; Straley, Kimberly; Kernytsky, Andrew; Liu, Wei; Gliser, Camelia; Yang, Hua; Gross, Stefan; Artin, Erin; Saada, Veronique; Mylonas, Elena; Quivoron, Cyril; Popovici-Muller, Janeta; Saunders, Jeffrey O.; Salituro, Francesco G.; Yan, Shunqi; Murray, Stuart; Wei, Wentao; Gao, Yi; Dang, Lenny; Dorsch, Marion; Agresta, Sam; Schenkein, David P.; Biller, Scott A.; Su, Shinsan M.; de Botton, Stephane; Yen, Katharine E.Science (Washington, DC, United States) (2013), 340 (6132), 622-626CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A no. of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small mol., AGI-6780, that potently and selectively inhibits the tumor-assocd. mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymol. anal. were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.(b) Yen, K.; Travins, J.; Wang, F.; David, M. D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; Chen, Y.; Nagaraja, R.; Choe, S.; Jin, L.; Konteatis, Z.; Cianchetta; Saunders, J. O.; Salituro, F. G.; Quivoron, C.; Opolon, P.; Bawa, O.; Saada, O.; Paci, A.; Broutin, S.; Bernard, O. A.; de Botton, S.; Marteyn, B. S.; Pilichowska, M.; Xu, Y. X.; Fang, C.; Jiang, F.; Wei, W.; Jin, S.; Silverman, L.; Liu, W.; Yang, H.; Dang, L.; Dorsch, M.; Penard-Lacronique, V.; Biller, S. A.; Su, S.-S. M. AG-221, A first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discovery 2017, 7, 478– 493, DOI: 10.1158/2159-8290.CD-16-1034[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFemurY%253D&md5=b83b3d82491d02befbde03aa392a6914AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 MutationsYen, Katharine; Travins, Jeremy; Wang, Fang; David, Muriel D.; Artin, Erin; Straley, Kimberly; Padyana, Anil; Gross, Stefan; De La Barre, Byron; Tobin, Erica; Chen, Yue; Nagaraja, Raj; Choe, Sung; Jin, Lei; Konteatis, Zenon; Cianchetta, Giovanni; Saunders, Jeffrey O.; Salituro, Francesco G.; Quivoron, Cyril; Opolon, Paule; Bawa, Olivia; Saada, Veronique; Paci, Angelo; Broutin, Sophie; Bernard, Olivier A.; de Botton, Stephane; Marteyn, Benoit S.; Pilichowska, Monika; Xu, Ying Xia; Fang, Cheng; Jiang, Fan; Wei, Wentao; Jin, Shengfang; Silverman, Lee; Liu, Wei; Yang, Hua; Dang, Lenny; Dorsch, Marion; Penard-Lacronique, Virginie; Biller, Scott A.; Su, Shin-San MichaelCancer Discovery (2017), 7 (5), 478-493CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematol. and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG prodn. and induced cellular differentiation in primary human IDH2 mutation-pos. acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clin. trials of AG-221 in patients with IDH2 mutation-pos. advanced hematol. malignancies. Significance: Mutations in IDH1/2 are identified in approx. 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclin. models and induces differentiation of malignant blasts, supporting its clin. development.
- 111Bhatia, C.; Yue, W. W.; Niesen, F.; Pilka, E.; Ugochukwu, E.; Savitsky, P.; Hozjan, V.; Roos, A. K.; Filippakopoulos, P.; Von Delft, F.; Heightman, T.; Arrowsmith, C.; Weigelt, J.; Edwards, A.; Bountra, C.; Opperman, U. 2WM3: Crystal structure of NmrA-like family domain containing protein 1 in complex with niflumic acid. Protein Data Bank, 2009, DOI: DOI: 10.2210/pdb2wm3/pdb .
- 112Blobaum, A. L.; Uddin, Md. J.; Felts, A. S.; Crews, B. C.; Rouzer, C. A.; Marnett, L. J. The 2′-trifluoromethyl analogue of indomethacin is a potent and selective COX-2 inhibitor. ACS Med. Chem. Lett. 2013, 4, 486– 490, DOI: 10.1021/ml400066a
- 113Sun, L.-Q.; Mull, E.; Zheng, B.; D’Andrea, S.; Zhao, Q.; Wang, A. X.; Sin, N.; Venables, B. L.; Sit, S.-Y.; Chen, Y.; Chen, J.; Cocuzza, A.; Bilder, D. M.; Mathur, A.; Rampulla, R.; Chen, B.-C.; Palani, T.; Ganesan, S.; Arunachalam, P. N.; Falk, P.; Levine, A.; Chen, C.; Friborg, J.; Yu, F.; Hernandez, D.; Sheaffer, A. K.; Knipe, J. O.; Han, Y.-H.; Schartman, R.; Donoso, M.; Mosure, K.; Sinz, M. W.; Zvyaga, T.; Rajamani, R.; Kish, K.; Tredup, J.; Klei, H. E.; Gao, Q.; Ng, A.; Mueller, L.; Grasela, D. M.; Adams, S.; Loy, J.; Levesque, P. C.; Sun, H.; Shi, H.; Sun, L.; Warner, W.; Li, D.; Zhu, J.; Wang, Y.-K.; Fang, H.; Cockett, M. I.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Discovery of a potent acyclic, tripeptidic, acyl sulfonamide inhibitor of hepatitis C virus NS3 protease as a back-up to asunaprevir with the potential for once-daily dosing. J. Med. Chem. 2016, 59, 8042– 8060, DOI: 10.1021/acs.jmedchem.6b00821[ACS Full Text
], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtl2rsrnK&md5=9d87037fcf23ef830e7ea02a6c6f2f8bDiscovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily DosingSun, Li-Qiang; Mull, Eric; Zheng, Barbara; D'Andrea, Stanley; Zhao, Qian; Wang, Alan Xiangdong; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Chen, Jie; Cocuzza, Anthony; Bilder, Donna M.; Mathur, Arvind; Rampulla, Richard; Chen, Bang-Chi; Palani, Theerthagiri; Ganesan, Sivakumar; Arunachalam, Pirama Nayagam; Falk, Paul; Levine, Steven; Chen, Chaoqun; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Sheaffer, Amy K.; Knipe, Jay O.; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W.; Zvyaga, Tatyana; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Ng, Alicia; Mueller, Luciano; Grasela, Dennis M.; Adams, Stephen; Loy, James; Levesque, Paul C.; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Wang, Ying-Kai; Fang, Hua; Cockett, Mark I.; Meanwell, Nicholas A.; McPhee, Fiona; Scola, Paul M.Journal of Medicinal Chemistry (2016), 59 (17), 8042-8060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir is described. The objective of this work was the identification of a drug with antiviral properties and toxicol. parameters similar to asunaprevir, but with a preclin. pharmacokinetic (PK) profile that was predictive of once-daily dosing. Crit. to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compds. that, like asunaprevir, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 from clin. trials. Structure-activity relationships (SARs) at each of the structural subsites in asunaprevir were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Addnl. modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 I. - 114(a) Phillips, M. A.; Gujjar, R.; Malmquist, N. A.; White, J.; El Mazouni, F.; Baldwin, J.; Rathod, P. K. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite, Plasmodium falciparum. J. Med. Chem. 2008, 51, 3649– 3653, DOI: 10.1021/jm8001026[ACS Full Text.
], [CAS], Google Scholar114ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXms1Gisbs%253D&md5=7bdbdc57d346ef3290623adc4aed89eeTriazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite Plasmodium falciparumPhillips, Margaret A.; Gujjar, Ramesh; Malmquist, Nicholas A.; White, John; El Mazouni, Farah; Baldwin, Jeffrey; Rathod, Pradipsinh K.Journal of Medicinal Chemistry (2008), 51 (12), 3649-3653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor I that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogs were produced by an inexpensive three-step synthesis, and the series showed good assocn. between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).(b) Gujjar, R.; Marwaha, A.; El Mazouni, F.; White, J.; White, K. L.; Creason, S.; Shackleford, D. M.; Baldwin, J.; Charman, W. N.; Buckner, F. S.; Charman, S.; Rathod, P. K.; Phillips, M. A. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem. 2009, 52, 1864– 1872, DOI: 10.1021/jm801343r[ACS Full Text.
], [CAS], Google Scholar114bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtlenuro%253D&md5=773ca17ea78a4f833c092c211c90c199Identification of a Metabolically Stable Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Antimalarial Activity in MiceGujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah; White, John; White, Karen L.; Creason, Sharon; Shackleford, David M.; Baldwin, Jeffrey; Charman, William N.; Buckner, Frederick S.; Charman, Susan; Rathod, Pradipsinh K.; Phillips, Margaret A.Journal of Medicinal Chemistry (2009), 52 (7), 1864-1872CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compds. contg. naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metab. in human liver microsomes and which showed prolonged exposure in mice. Compd. 21 (DSM74), contg. p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.(c) Deng, X.; Gujjar, R.; El Mazouni, F.; Kaminsky, W.; Malmquist, N. A.; Goldsmith, E. J.; Rathod, P. K.; Phillips, M. A. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J. Biol. Chem. 2009, 284, 26999– 27009, DOI: 10.1074/jbc.M109.028589[Crossref], [PubMed], [CAS], Google Scholar.114chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFCgsL%252FM&md5=0b6b089104abafd748010651b964494eStructural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffoldsDeng, Xiaoyi; Gujjar, Ramesh; El Mazouni, Farah; Kaminsky, Werner; Malmquist, Nicholas A.; Goldsmith, Elizabeth J.; Rathod, Pradipsinh K.; Phillips, Margaret A.Journal of Biological Chemistry (2009), 284 (39), 26999-27009CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure detn. of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chem. classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small mol. crystallog., is that the triazolopyrimidines populate a resonance form that promotes charge sepn. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.(d) Coteron, J. M.; Marco, M.; Esquivias, J.; Deng, X.; White, K. L.; White, J.; Koltun, M.; El Mazouni, F.; Kokkonda, S.; Katneni, K.; Bhamidipati, R.; Shackleford, D. M.; Angulo-Barturen, I.; Ferrer, S. B.; Jiménez-Díaz, M. B.; Gamo, F.-J.; Goldsmith, E. J.; Charman, W. N.; Bathurst, I.; Floyd, D.; Matthews, D.; Burrows, J. N.; Rathod, P. K.; Charman, S. A.; Phillips, M. A. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J. Med. Chem. 2011, 54, 5540– 5561, DOI: 10.1021/jm200592f[ACS Full Text.
], [CAS], Google Scholar114dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXovVehsbg%253D&md5=d92f71aeda04fbbbbcd8905a657df011Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate PotentialCoteron, Jose M.; Marco, Maria; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L.; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M.; Angulo-Barturen, Inigo; Ferrer, Santiago B.; Jimenez-Diaz, Maria Belen; Gamo, Francisco-Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A.Journal of Medicinal Chemistry (2011), 54 (15), 5540-5561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chem. program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compd. has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compd. toward clin. candidate status.(e) Deng, X.; Kokkonda, S.; El Mazouni, F.; White, J.; Burrows, J. N.; Kaminsky, W.; Charman, S. A.; Matthews, D.; Rathod, P. K.; Phillips, M. A. Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J. Med. Chem. 2014, 57, 5381– 5394, DOI: 10.1021/jm500481t[ACS Full Text.
], [CAS], Google Scholar114ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXns1Chs74%253D&md5=abfc8df6c8510665049e65338732acf0Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase InhibitorsDeng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah; White, John; Burrows, Jeremy N.; Kaminsky, Werner; Charman, Susan A.; Matthews, David; Rathod, Pradipsinh K.; Phillips, Margaret A.Journal of Medicinal Chemistry (2014), 57 (12), 5381-5394CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. The authors describe a detailed anal. of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. The authors show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. The authors conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. The authors' studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.(f) Phillips, M. A.; Lotharius, J.; Marsh, K.; White, J.; Dayan, A.; White, K. L.; Njoroge, J. W.; El Mazouni, F.; Lao, Y.; Kokkonda, S.; Tomchick, D. R.; Deng, X.; Laird, T.; Bhatia, S. N.; March, S.; Ng, C. L.; Fidock, D. A.; Wittlin, S.; Lafuente-Monasterio, M.; Benito, F. J.; Alonso, L. M.; Martinez, M. S.; Jimenez-Diaz, M. B.; Bazaga, S. F.; Angulo-Barturen, I.; Haselden, J. N.; Louttit, J.; Cui, Y.; Sridhar, A.; Zeeman, A. M.; Kocken, C.; Sauerwein, R.; Dechering, K.; Avery, V. M.; Duffy, S.; Delves, M.; Sinden, R.; Ruecker, A.; Wickham, K. S.; Rochford, R.; Gahagen, J.; Iyer, L.; Riccio, E.; Mirsalis, J.; Bathhurst, I.; Rueckle, T.; Ding, X.; Campo, B.; Leroy, D.; Rogers, M. J.; Rathod, P. K.; Burrows, J. N.; Charman, S. A. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl. Med. 2015, 7 (296), 296ra111, DOI: 10.1126/scitranslmed.aaa6645 .(g) Phillips, M. A.; White, K. L.; Kokkonda, S.; Deng, X.; White, J.; El Mazouni, F.; Marsh, K.; Tomchick, D. R.; Manjalanagara, K.; Rudra, K. R.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Shackleford, D. M.; Chiu, F. C. K. M.; Campbell, M.; Jimenez-Diaz, M. B.; Ferrer Bazaga, S.; Angulo-Barturen, I.; Santos Martinez, M.; Lafuente-Monasterio, M.; Kaminsky, W.; Silue, K.; Zeeman, A.-M.; Kocken, C.; Leroy, D.; Blasco, B.; Rossignol, E.; Rueckle, T.; Matthews, D.; Burrows, J. N.; Waterson, D.; Palmer, M. J.; Rathod, P. K.; Charman, S. A. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect. Dis. 2016, 2, 945– 957, DOI: 10.1021/acsinfecdis.6b00144[ACS Full Text
], [CAS], Google Scholar114ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWmtbjJ&md5=df58b9d21b75ad84d6181d42a2341e60A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of MalariaPhillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Shackleford, David M.; Chiu, Francis C. K.; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Inigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N.; Waterson, David; Palmer, Michael J.; Rathod, Pradipsinh K.; Charman, Susan A.ACS Infectious Diseases (2016), 2 (12), 945-957CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor I of the Plasmodium enzyme is currently in clin. development. With the goal of identifying a backup compd. to I, the authors explored replacement of the SF5-aniline moiety of I with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of II, which has improved soly., lower intrinsic clearance and increased plasma exposure after oral dosing compared to I, while maintaining a long predicted human half-life. Its improved phys. and chem. properties will allow it to be formulated more readily than I. II showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly II showed equal activity against both P. falciparum and P. vivax field isolates, while I was more active on P. falciparum. II has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclin. development candidate. - 115Martin, M. P.; Zhu, J.-Y.; Lawrence, H. R.; Pireddu, R.; Luo, Y.; Alam, R.; Ozcan, S.; Sebti, S. M.; Lawrence, N. J.; Schönbrunn, E. A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. ACS Chem. Biol. 2012, 7, 698– 706, DOI: 10.1021/cb200508b[ACS Full Text
], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xntlaguw%253D%253D&md5=af1e536bcfae58a76762e85f4b0b9829A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora AMartin, Mathew P.; Zhu, Jin-Yi; Lawrence, Harshani R.; Pireddu, Roberta; Luo, Yunting; Alam, Riazul; Ozcan, Sevil; Sebti, Said M.; Lawrence, Nicholas J.; Schonbrunn, ErnstACS Chemical Biology (2012), 7 (4), 698-706CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small mol. inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced-dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three-dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with elec. dipoles. - 116(a) Clark, J.; Perrin, D. D. Prediction of the strengths of organic bases. Q. Rev., Chem. Soc. 1964, 18, 295– 320, DOI: 10.1039/qr9641800295[Crossref], [CAS], Google Scholar.116ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXis1Cl&md5=5b4002e8c9f42ac111f5fc9730198a22Prediction of the strengths of organic basesClark, Jim; Perrin, D. D.(1964), 18 (3), 295-320 ISSN:.A review with 44 references.(b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059[Crossref], [PubMed], [CAS], Google Scholar116bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFemsbY%253D&md5=478b70744312c01d3a43cf435d9598dePredicting and tuning physicochemical properties in lead optimization: amine basicitiesMorgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, KlausChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
- 117Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R. Application of the Goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: balancing pKa and steric effects in the optimization of 3-methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-fluorination. J. Med. Chem. 2006, 49, 2939– 2952, DOI: 10.1021/jm051262k[ACS Full Text
], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjsVajtb4%253D&md5=468ae2a5832e69d751628ca743ef951cApplication of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-FluorinationGrunewald, Gary L.; Seim, Mitchell R.; Lu, Jian; Makboul, Mariam; Criscione, Kevin R.Journal of Medicinal Chemistry (2006), 49 (10), 2939-2952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α2-adrenoceptor. Fluorination of the Me group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a redn. in affinity for the α2-adrenoceptor. However, increased fluorination also results in a redn. in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochem. evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the α2-adrenoceptor, while the latter were devoid of α2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity vs. the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency vs. the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the α2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α2-adrenoceptor. This seems to be the first successful use of the β-fluorination of aliph. amines to impart selectivity to a pharmacol. agent while maintaining potency at the site of interest. - 118Spahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017, 355, 966– 969, DOI: 10.1126/science.aai8636[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsVCgs7k%253D&md5=719809495aec8c3ac9e60429c9edea98A nontoxic pain killer designed by modeling of pathological receptor conformationsSpahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C.Science (Washington, DC, United States) (2017), 355 (6328), 966-969CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathol. (rather than physiol.) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissocn. const., selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissocn. by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
- 119(a) Cox, C. D.; Coleman, P. J.; Breslin, M. J.; Whitman, D. B.; Garbaccio, R. M.; Fraley, M. E.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Lobell, R. B.; Tao, W.; Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber, H. E.; Torrent, M.; Prueksaritanont, T.; Li, C.; Slaughter, D. E.; Mahan, E.; Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J. Med. Chem. 2008, 51, 4239– 4252, DOI: 10.1021/jm800386y[ACS Full Text.
], [CAS], Google Scholar119ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsl2rs7s%253D&md5=283d7227309cbe634f18a640c8085090Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory CancerCox, Christopher D.; Coleman, Paul J.; Breslin, Michael J.; Whitman, David B.; Garbaccio, Robert M.; Fraley, Mark E.; Buser, Carolyn A.; Walsh, Eileen S.; Hamilton, Kelly; Schaber, Michael D.; Lobell, Robert B.; Tao, Weikang; Davide, Joseph P.; Diehl, Ronald E.; Abrams, Marc T.; South, Vicki J.; Huber, Hans E.; Torrent, Maricel; Prueksaritanont, Thomayant; Li, Chunze; Slaughter, Donald E.; Mahan, Elizabeth; Fernandez-Metzler, Carmen; Yan, Youwei; Kuo, Lawrence C.; Kohl, Nancy E.; Hartman, George D.Journal of Medicinal Chemistry (2008), 51 (14), 4239-4252CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations assocd. with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compds. from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that β-fluorination modulated the pKa of the piperidine nitrogen and reduced Pgp efflux, but the resulting compd. (14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compd. 30 that has an optimal in vitro and metabolic profile. Compd. 30 (MK-0731) was recently studied in a phase I clin. trial in patients with taxane-refractory solid tumors.(b) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein. Bioorg. Med. Chem. Lett. 2007, 17, 2697– 2702, DOI: 10.1016/j.bmcl.2007.03.006 - 120McDonald, I. M.; Mate, R. A.; Zusi, F. C.; Huang, H.; Post-Munson, D. J.; Ferrante, M. A.; Gallagher, L.; Bertekap, R. L., Jr.; Knox, R. J.; Robertson, B. J.; Harden, D. G.; Morgan, D. G.; Lodge, N. J.; Dworetzky, S. I.; Olson, R. E.; Macor, J. E. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists. Bioorg. Med. Chem. Lett. 2013, 23, 1684– 1688, DOI: 10.1016/j.bmcl.2013.01.070
- 121Sun, H.; Xia, M.; Shahane, S. A.; Jadhav, A.; Austin, C. P.; Huang, R. Are hERG channel blockers also phospholipidosis inducers?. Bioorg. Med. Chem. Lett. 2013, 23, 4587– 4590, DOI: 10.1016/j.bmcl.2013.06.034[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFShu73M&md5=20f829eba492b0380eadb33ebe5bb179Are hERG channel blockers also phospholipidosis inducers?Sun, Hongmao; Xia, Menghang; Shahane, Sampada A.; Jadhav, Ajit; Austin, Christopher P.; Huang, RuiliBioorganic & Medicinal Chemistry Letters (2013), 23 (16), 4587-4590CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Both pharmacophore models of the human ether-a-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/pos. charged center, so it is interesting to investigate the overlap between the ligand chem. spaces of both targets. The authors have assayed over 4000 non-redundant drug-like compds. for both their hERG inhibitory activity and PLD inducing potential in a quant. high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compds. identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compds. were pos. charged. Among the 48 compds. that induced PLD without inhibiting hERG channel, 24 compds. (50.0%) carried steroidal structures. According to the authors' results, hERG channel blockers and PLD inducers share a large chem. space. In addn., a pos. charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.
- 122Nakajima, Y.; Inoue, T.; Nakai, K.; Mukoyoshi, K.; Hamaguchi, H.; Hatanaka, K.; Sasaki, H.; Tanaka, A.; Takahashi, F.; Kunikawa, S.; Usuda, H.; Moritomo, A.; Higashi, Y.; Inami, M.; Shirakami, S. Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3. Bioorg. Med. Chem. 2015, 23, 4871– 4883, DOI: 10.1016/j.bmc.2015.05.034[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFOktrc%253D&md5=378ff172c2374ea40d784c59f1e192d7Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3Nakajima, Yutaka; Inoue, Takayuki; Nakai, Kazuo; Mukoyoshi, Koichiro; Hamaguchi, Hisao; Hatanaka, Keiko; Sasaki, Hiroshi; Tanaka, Akira; Takahashi, Fumie; Kunikawa, Shigeki; Usuda, Hiroyuki; Moritomo, Ayako; Higashi, Yasuyuki; Inami, Masamichi; Shirakami, ShoheiBioorganic & Medicinal Chemistry (2015), 23 (15), 4871-4883CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivs. are promising candidates for treating such diseases. In chem. modification of lead compd. (I), the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addn., modulation of phys. properties such as mol. lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. The authors' optimization study gave compd. 31 (4-[[(3S,4R)-1-(5-cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide), which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
- 123Rombouts, F. J. R.; Tresadern, G.; Delgado, O.; Martínez-Lamenca, C.; Van Gool, M.; García-Molina, A.; Alonso de Diego, S. A.; Oehlrich, D.; Prokopcova, H.; Alonso, J. M.; Austin, N.; Borghys, H.; Van Brandt, S.; Surkyn, M.; De Cleyn, M.; Vos, A.; Alexander, R.; Macdonald, G.; Moechars, D.; Gijsen, H.; Trabanco, A. A. 1,4-Oxazine β-secretase 1 (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads. J. Med. Chem. 2015, 58, 8216– 8235, DOI: 10.1021/acs.jmedchem.5b01101[ACS Full Text
], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFWktL3L&md5=d3563a26a17a1c86c45a4f99b18be2511,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant LeadsRombouts, Frederik J. R.; Tresadern, Gary; Delgado, Oscar; Martinez-Lamenca, Carolina; Van Gool, Michiel; Garcia-Molina, Aranzazu; Alonso de Diego, Sergio A.; Oehlrich, Daniel; Prokopcova, Hana; Alonso, Jose Manuel; Austin, Nigel; Borghys, Herman; Van Brandt, Sven; Surkyn, Michel; De Cleyn, Michel; Vos, Ann; Alexander, Richard; Macdonald, Gregor; Moechars, Dieder; Gijsen, Harrie; Trabanco, Andres A.Journal of Medicinal Chemistry (2015), 58 (20), 8216-8235CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)1,4-Oxazines are presented, which show good in vitro inhibition in enzymic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and esp. P-glycoprotein efflux. This led to compds. which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, resp., in mouse and dog models. The amyloid lowering potential of these mols. makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease. - 124Scattolin, T.; Deckers, K.; Schoenebeck, F. Efficient synthesis of trifluoromethyl amines through a formal umpolung strategy from the bench-stable precursor (Me4N)SCF3. Angew. Chem., Int. Ed. 2017, 56, 221– 224, DOI: 10.1002/anie.201609480[Crossref], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVGqtr7E&md5=5c26bd9e2281d4e3ecd33bbdeb6a087aEfficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3Scattolin, Thomas; Deckers, Kristina; Schoenebeck, FranziskaAngewandte Chemie, International Edition (2017), 56 (1), 221-224CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Reported herein is the one-pot synthesis of trifluoromethylated amines at room temp. using the bench-stable (Me4N)SCF3 reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3 with the amine, giving quant. formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug mols.
- 125Asahina, Y.; Araya, I.; Iwase, K.; Iinuma, F.; Hosaka, M.; Ishizaki, T. Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent. J. Med. Chem. 2005, 48, 3443– 3446, DOI: 10.1021/jm040204g
- 126Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma, A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang, X.; Wick, M. M.; Zhang, X.; Lum, R. T. Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg. Med. Chem. Lett. 1997, 7, 2697– 2702, DOI: 10.1016/S0960-894X(97)10076-2
- 127Miao, Z.; Zhu, L.; Dong, G.; Zhuang, C.; Wu, Y.; Wang, S.; Guo, Z.; Liu, Y.; Wu, S.; Zhu, S.; Fang, K.; Yao, J.; Li, J.; Sheng, C.; Zhang, W. A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors. J. Med. Chem. 2013, 56, 7902– 7910, DOI: 10.1021/jm400906z[ACS Full Text
], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFarsrzE&md5=c99ef47778bdea1041e131efdb8fdbfaA New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S) 21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I InhibitorsMiao, Zhenyuan; Zhu, Lingjian; Dong, Guoqiang; Zhuang, Chunlin; Wu, Yuelin; Wang, Shengzheng; Guo, Zizao; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Fang, Kun; Yao, Jianzhong; Li, Jian; Sheng, Chunquan; Zhang, WannianJournal of Medicinal Chemistry (2013), 56 (20), 7902-7910CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Lactone is a common structural motif in biol. active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin deriv., (20S,21S)-7-Cyclohexyluorocamptothecin, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. The authors' results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone. - 128Wipf, P.; Henninger, T. C.; Geib, S. J. Methyl- and (trifluoromethyl)alkene peptide isosteres: synthesis and evaluation of their potential as β-turn promoters and peptide mimetics. J. Org. Chem. 1998, 63, 6088– 6089, DOI: 10.1021/jo981057v[ACS Full Text
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- 130Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies. Org. Biomol. Chem. 2007, 5, 1151– 1157, DOI: 10.1039/b701559c[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvVakurc%253D&md5=64147d262b88033f13559044af6815ffChiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studiesCouve-Bonnaire, Samuel; Cahard, Dominique; Pannecoucke, XavierOrganic & Biomolecular Chemistry (2007), 5 (8), 1151-1157CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The replacement of the amide bond in a peptide backbone is a promising strategy in peptidomimetic drug research. Over the various amide bond surrogates, the fluoroolefin moiety has been successfully developed as an effective mimic. Today, fluorine-contg. compds. account for a large proportion of new active mols. in life sciences. The synthesis of fluoroolefin peptide mimics is not a trivial task and innovative approaches often need to be addressed, in particular for the stereocontrol of the double bond configuration and the chiral centers adjacent to the fluoroalkene. These fluorinated peptidomimetics have been synthesized and evaluated as metabolically stable and/or conformationally constrained analogs of enzyme inhibitors, and as tools for probing the function, structure, and binding process of receptors.
- 131Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T. H.; Blais, V.; Guérin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-ψ[(Z)CF═CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimetic. ACS Chem. Neurosci. 2017, 8, 40– 49, DOI: 10.1021/acschemneuro.6b00163[ACS Full Text
], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSisLnI&md5=893e2b2d560b04eebac0139a6830c42bSynthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimeticNadon, Jean-Francois; Rochon, Kristina; Grastilleur, Sebastien; Langlois, Guillaume; Dao, Thi Thanh Ha; Blais, Veronique; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.ACS Chemical Neuroscience (2017), 8 (1), 40-49CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepd. and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF=CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane exts. of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the elec. induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biol. activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes. - 132Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A. Synthesis and opioid activity of Tyr1-Ψ(Z)CF═CH]-Gly2 and Tyr1-Ψ(S)/(R)CF3CH-NH]-Gly2 Leu enkephalin fluorinated peptidomimetics. ChemMedChem 2017, 12, 571– 576, DOI: 10.1002/cmdc.201700103
- 133Rogers, M. T. The electric moments of some unsaturated aldehydes, ethers and halogen compounds. J. Am. Chem. Soc. 1947, 69, 1243– 1246, DOI: 10.1021/ja01198a003
- 134(a) Kobayakawa, T.; Narumi, T.; Tamamura, H. Remote stereoinduction in the organocuprate-mediated allylic alkylation of allylic gem-dichlorides: highly diastereoselective synthesis of (Z)-chloroalkene dipeptide isosteres. Org. Lett. 2015, 17, 2302– 2305, DOI: 10.1021/acs.orglett.5b00611 .(b) Waelchli, R.; Gamse, R.; Bauer, W.; Lier, E.; Feyen, J. H. M. Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogues of hPTH(1–36) fragment. Bioorg. Med. Chem. Lett. 1996, 6, 1151– 1156, DOI: 10.1016/0960-894X(96)00188-6[Crossref], [CAS], Google Scholar.134bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjsVCnurg%253D&md5=e1071148ed8dd3c0d0b32d3e6fc1bfb4Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogs of hPTH(1-36) fragmentWaelchli, Rudolf; Gamse, Rainer; Bauer, Wilfried; Meigel, Harald; Lier, Edouard; Feyen, Jean H. M.Bioorganic & Medicinal Chemistry Letters (1996), 6 (10), 1151-1156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)A series of human parathyroid hormone (1-36) [hPTH(1-36)] analogs were prepd. to study the role of the first peptide bond between residues Ser1-Val2. Some of these analogs were found to show high affinity binding in intact opossum kidney (OK-1) cells and were very active in their ability to stimulate adenylate cyclase prodn. in intact OK-1 cells, rat UMR-106-06 osteosarcoman cells and SaOS-2 human osteosarcoma cells.(c) Kobayakawa, T.; Matsuzaki, Y.; Hozumi, K.; Nomura, W.; Nomizu, M.; Tamamura, H. Synthesis of a Chloroalkene dipeptide isostere-containing peptidomimetic and its biological application. ACS Med. Chem. Lett. 2018, 9, 6– 10, DOI: 10.1021/acsmedchemlett.7b00234[ACS Full Text
], [CAS], Google Scholar134chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVeltrrO&md5=7840922bbd033792a553be95db17af3dSynthesis of a chloroalkene dipeptide isostere-containing peptidomimetic and its biological applicationKobayakawa, Takuya; Matsuzaki, Yudai; Hozumi, Kentaro; Nomura, Wataru; Nomizu, Motoyoshi; Tamamura, HirokazuACS Medicinal Chemistry Letters (2018), 9 (1), 6-10CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The first rapid and efficient chem. synthesis of a cyclic Arg-Gly-Asp (RGD) peptide contg. a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an N-Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-contg. cyclic RGD peptide was successful, and the synthesized CADI-contg. peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide. - 135Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry, N. A.; Weber, A. E. Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 2409– 2413, DOI: 10.1016/j.bmcl.2008.02.050[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjvFyktL0%253D&md5=09731e5d01cac5602e84baf81e10e890Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitorsEdmondson, Scott D.; Wei, Lan; Xu, Jinyou; Shang, Jackie; Xu, Shiyao; Pang, Jianmei; Chaudhary, Ashok; Dean, Dennis C.; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Patel, Reshma A.; Patel, Sangita B.; Scapin, Giovanna; Wu, Joseph K.; Beconi, Maria G.; Thornberry, Nancy A.; Weber, Ann E.Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2409-2413CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The synthesis, selectivity, rat pharmacokinetic profile, and drug metab. profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
- 136(a) Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics. Bioorg. Med. Chem. Lett. 2012, 22, 2938– 2942, DOI: 10.1016/j.bmcl.2012.02.051[Crossref], [PubMed], [CAS], Google Scholar.136ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktV2qtLk%253D&md5=513fc896ce045cbf1a236d75bb75b29cInhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimeticsChang, Wonsuk; Mosley, Ralph T.; Bansal, Shalini; Keilman, Meg; Lam, Angela M.; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2938-2942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-mol. hydrogen bonds were a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin contg. inhibitor exhibited picomolar activity (EC50 = 79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.(b) Belema, M.; Lopez, O. D.; Bender, J. A.; Romine, J. L.; St. Laurent, D. R.; Langley, D. R.; Lemm, J. A.; O’Boyle, D. R., II; Sun, J.-H.; Wang, C.; Fridell, R. A.; Meanwell, N. A. The discovery and development of hepatitis C virus NS5A replication complex inhibitors. J. Med. Chem. 2014, 57, 1643– 1672, DOI: 10.1021/jm401793m[ACS Full Text
], [CAS], Google Scholar136bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslygsbk%253D&md5=cc92046f9edcb633b433a0e6a4ac3fecDiscovery and Development of Hepatitis C Virus NS5A Replication Complex InhibitorsBelema, Makonen; Lopez, Omar D.; Bender, John A.; Romine, Jeffrey L.; St. Laurent, Denis R.; Langley, David R.; Lemm, Julie A.; O'Boyle, Donald R., II; Sun, Jin-Hua; Wang, Chunfu; Fridell, Robert A.; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2014), 57 (5), 1643-1672CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chem. studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compds. currently in clin. trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogs that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clin. trials with HCV NS5A RCIs. - 137Hollenstein, M.; Leumann, C. J. Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA. J. Org. Chem. 2005, 70, 3205– 3217, DOI: 10.1021/jo047753e[ACS Full Text
], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitVWrtLo%253D&md5=120463d7cacde3615181a5948949968fFluorinated Olefinic Peptide Nucleic Acid: Synthesis and Pairing Properties with Complementary DNAHollenstein, Marcel; Leumann, Christian J.Journal of Organic Chemistry (2005), 70 (8), 3205-3217CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The fluorinated olefinic peptide nucleic acid (F-OPA) system was designed as a peptide nucleic acid (PNA) analog in which the base carrying amide moiety was replaced by an isostructural and isoelectrostatic fluorinated C-C double bond, locking the nucleobases in one of the two possible rotameric forms. By comparison of the base-pairing properties of this analog with its nonfluorinated analog OPA and PNA, the authors attempted a closer understanding of the role of this amide function in complementary DNA recognition. Here, the synthesis of the F-OPA monomer building blocks contg. the nucleobases A, T, and G according to the MMTr/Acyl protecting group scheme is presented. Key steps are a selective desymmetrization of the double bond in the monomer precursor via lactonization as well as a highly regioselective Mitsunobu reaction for the introduction of the bases. PNA decamers contg. single F-OPA mutations and fully modified F-OPA decamers and pentadecamers contg. the bases A and T were synthesized by solid-phase peptide chem., and their hybridization properties with complementary parallel and antiparallel DNA were assessed by UV melting curves and CD spectroscopic methods. The stability of the duplexes formed by the decamers contg. single (Z)-F-OPA modifications with parallel and antiparallel DNA was found to be strongly dependent on their position in the sequence with Tm values ranging from +2.4 to -8.1°/modification as compared to PNA. Fully modified F-OPA decamers and pentadecamers were found to form parallel duplexes with complementary DNA with reduced stability compared to PNA or OPA. An asym. F-OPA pentadecamer was found to form a stable self-complex (Tm ∼ 65°) of unknown structure. The generally reduced affinity to DNA may therefore be due to an increased propensity for self-aggregation. - 138(a) Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R. M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J. Med. Chem. 2003, 46, 4050– 4062, DOI: 10.1021/jm030131l .(b) Parlow, J. J.; Stevens, A. M.; Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4297– 4312, DOI: 10.1021/jm030233b[ACS Full Text.
], [CAS], Google Scholar138bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1Kmsrg%253D&md5=1541bf4617e1a58623eb752b6417007eSynthesis and Crystal Structures of Substituted Benzenes and Benzoquinones as Tissue Factor VIIa InhibitorsParlow, John J.; Stevens, Anna M.; Stegeman, Roderick A.; Stallings, William C.; Kurumbail, Ravi G.; South, Michael S.Journal of Medicinal Chemistry (2003), 46 (20), 4297-4312CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Several multistep syntheses of substituted benzenes are reported. The benzene analogs were designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue Factor VIIa enzyme. A variety of chem. transformations including nucleophilic addns., reductive aminations, Stille couplings, and polymer-assisted soln.-phase (PASP) techniques were used to prep. key intermediates and final products. The initial analogs identified some weakly active compds. which ultimately led to a 340 nM (IC50) tissue Factor VIIa inhibitor with selectivity over other related enzymes. The structure-activity relationship of these inhibitors and the synthetic progression from the discovery of the lead compd. to the development of potent analogs will be discussed. The X-ray crystal structures of 3'-amino-N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide and N-[[4-(aminoiminomethyl)phenyl]methyl]-5-[(1-methylethyl)amino]-3,6-dioxo-2-phenyl-1,4-cyclohexadiene-1-acetamide inhibitors complexed with the TF/VIIa enzyme will also be described. Other compds. thus prepd. and screened included N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-2,6-difluoro-3-[[(phenylmethyl)sulfonyl]amino]benzeneacetamide.(c) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex. Bioorg. Med. Chem. Lett. 2003, 13, 3721– 3725, DOI: 10.1016/j.bmcl.2003.08.002 .(d) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4696– 4701, DOI: 10.1021/jm0301686[ACS Full Text
], [CAS], Google Scholar138dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1Kktrc%253D&md5=d463973a0ba48427f8131ae032c0637bDesign, Synthesis, and Crystal Structure of Selective 2-Pyridone Tissue Factor VIIa InhibitorsParlow, John J.; Kurumbail, Ravi G.; Stegeman, Roderick A.; Stevens, Anna M.; Stallings, William C.; South, Michael S.Journal of Medicinal Chemistry (2003), 46 (22), 4696-4701CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Targeted 2-pyridones were selected as tissue factor VIIa inhibitors and prepd. from 2,6-dibromopyridine via a multistep synthesis. A variety of chem. transformations, including regioselective nucleophilic addn., selective nitrogen alkylation, and a Suzuki coupling, afforded the targeted tissue factor VIIa inhibitors. The pyridone core was selected as a replacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue factor VIIa enzyme. These compds. were tested in several serine protease enzyme assays involved in the coagulation cascade exhibiting modest activity on tissue factor VIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structure of one inhibitor bound to tissue factor VIIa was obtained and will be described. Compds. thus prepd. and tested were 3-amino-5-[1-[2-[[[4-(aminoiminomethyl)phenyl]methyl]amino]-2-oxoethyl]-1,6-dihydro-5-[(1-methylethyl)amino]-6-oxo-2-pyridinyl]benzoic acid and N-[[4-(aminoiminomethyl)phenyl]methyl]-6-(3,5-diaminophenyl)-3-[(1-methylethyl)amino]-2-oxo-1(2H)-pyridineacetamide. - 139(a) Lee, L.; Kreutter, K. D.; Pan, W.; Crysler, C.; Spurlino, J.; Player, M. R.; Tomczuk, B.; Lu, T. 2-(2-Chloro-6-fluorophenyl)-acetamides as potent thrombin inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6266– 6269, DOI: 10.1016/j.bmcl.2007.09.013 .(b) Kreutter, K. D.; Lu, T.; Lee, L.; Giardino, E. C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.; Haertlein, B. J.; Mohan, V.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; McMillan, M.; Spurlino, J. C.; Huebert, N. D.; Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Player, M. R. Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg. Med. Chem. Lett. 2008, 18, 2865– 2870, DOI: 10.1016/j.bmcl.2008.03.087 .(c) Nantermet, P. G.; Burgey, C. S.; Robinson, K. A.; Pellicore, J. M.; Newton, C. L.; Deng, J. M.; Selnick, H. G.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Miller-Stein, C.; White, R. B.; Wong, B.; McMasters, D. R.; Wallace, A. A.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P.; Lyle, T. A. P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. Bioorg. Med. Chem. Lett. 2005, 15, 2771– 2775, DOI: 10.1016/j.bmcl.2005.03.110 .(d) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem. 2003, 46, 461– 473, DOI: 10.1021/jm020311f
- 140(a) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. The pKBHX database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. J. Med. Chem. 2009, 52, 4073– 4086, DOI: 10.1021/jm801331y[ACS Full Text.
], [CAS], Google Scholar140ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnsFKns7w%253D&md5=9ce4bea3e810752baba6ea5784b55ea0The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal ChemistsLaurence, Christian; Brameld, Ken A.; Graton, Jerome; Le Questel, Jean-Yves; Renault, EricJournal of Medicinal Chemistry (2009), 52 (14), 4073-4086CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The pKBHX database is presented, which corresponds to three main fields of data: hydrogen bond donor identification, thermodn. data and spectroscopic data. The pKBHX scale of hydrogen donor basicity differs considerable from the pKBH+ scale of proton transfer basicity. The hydrogen bond basicities of functional groups relevant to medicinal chem. and drug design is reviewed.(b) Kenny, P. W.; Montanari, C. A.; Prokopczyk, I. M.; Ribeiro, J. F.; Sartori, G. R. Hydrogen bond basicity prediction for medicinal chemistry design. J. Med. Chem. 2016, 59, 4278– 4288, DOI: 10.1021/acs.jmedchem.5b01946[ACS Full Text.
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Predictions are made for hydrogen bond basicity of fluorine in situations where relevant exptl. measurements are not available. It is shown how predicted pKBHX can be used to provide insight into the nature of bioisosterism and to profile heterocycles. Examples of pKBHX prediction for mol. structures with multiple, nonequivalent hydrogen bond acceptors are presented.(c) Pierce, A. C.; Sandretto, K. L.; Bemis, G. W. Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand binding. Proteins: Struct., Funct., Genet. 2002, 49, 567– 576, DOI: 10.1002/prot.10259[Crossref], [PubMed], [CAS], Google Scholar140chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XptlGru7c%253D&md5=641cc069501f9243df3ddc35cd3aa449Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand bindingPierce, Albert C.; Sandretto, Kathryn L.; Bemis, Guy W.Proteins: Structure, Function, and Genetics (2002), 49 (4), 567-576CODEN: PSFGEY; ISSN:0887-3585. (Wiley-Liss, Inc.)Although the hydrogen bond is known to be an important mediator of intermol. interactions, there has yet to be an anal. of the role of CH···O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of arom. ligands in 184 kinase crystal structures and 358 high-resoln. structures from the Protein Data Bank. CH groups adjacent to the pos. charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other arom. CH groups do not exhibit these characteristics. Ab initio calcns. reveal a considerable range of CH···O hydrogen bonding potentials among different arom. ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH···O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various arom. CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity anal. - 141Anilkumar, G. N.; Lesburg, C. A.; Selyutin, O.; Rosenblum, S. B.; Zeng, Q.; Jiang, Y.; Chan, T.-Y.; Pu, H.; Vaccaro, H.; Wang, L.; Bennett, F.; Chen, K. X.; Duca, J.; Gavalas, S.; Huang, Y.; Pinto, P.; Sannigrahi, M.; Velazquez, F.; Venkatraman, S.; Vibulbhan, B.; Agrawal, S.; Butkiewicz, N.; Feld, B.; Ferrari, E.; He, Z.; Jiang, C.-k.; Palermo, R. E.; Mcmonagle, P.; Huang, H.-C.; Shih, N.-Y.; Njoroge, G.; Kozlowski, J. A. I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles. Bioorg. Med. Chem. Lett. 2011, 21, 5336– 5341, DOI: 10.1016/j.bmcl.2011.07.021[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKis7zO&md5=0934657e3c8029bab0a01ea2c5113832I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocyclesAnilkumar, Gopinadhan N.; Lesburg, Charles A.; Selyutin, Oleg; Rosenblum, Stuart B.; Zeng, Qingbei; Jiang, Yueheng; Chan, Tin-Yau; Pu, Haiyan; Vaccaro, Henry; Wang, Li; Bennett, Frank; Chen, Kevin X.; Duca, Jose; Gavalas, Stephen; Huang, Yuhua; Pinto, Patrick; Sannigrahi, Mousumi; Velazquez, Francisco; Venkatraman, Srikanth; Vibulbhan, Bancha; Agrawal, Sony; Butkiewicz, Nancy; Feld, Boris; Ferrari, Eric; He, Zhiqing; Jiang, Chuan-kui; Palermo, Robert E.; McMonagle, Patricia; Huang, H.-C.; Shih, Neng-Yang; Njoroge, George; Kozlowski, Joseph A.Bioorganic & Medicinal Chemistry Letters (2011), 21 (18), 5336-5341CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead I (NS5B IC50 = 0.9 μM, replicon EC50 >100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in lead carboxyindoles II (NS5B IC50 = 0.032 μM, replicon EC50 = 1.4 μM) and III (NS5B IC50 = 0.017 μM, replicon EC50 = 0.3 μM) with improved enzyme and replicon activity.
- 142Adams, M. E.; Wallace, M. B.; Kanouni, T.; Scorah, N.; O’Connell, S. M.; Miyake, H.; Shi, L.; Halkowycz, P.; Zhang, L.; Dong, Q. Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy. Bioorg. Med. Chem. Lett. 2012, 22, 2411– 2414, DOI: 10.1016/j.bmcl.2012.02.026
- 143(a) Isshiki, Y.; Kohchi, Y.; Iikura, H.; Matsubara, Y.; Asoh, K.; Murata, T.; Kohchi, M.; Mizuguchi, E.; Tsujii, S.; Hattori, K.; Miura, T.; Yoshimura, Y.; Aida, S.; Miwa, M.; Saitoh, R.; Murao, N.; Okabe, H.; Belunis, C.; Janson, C.; Lukacs, C.; Schück, V.; Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg. Med. Chem. Lett. 2011, 21, 1795– 1801, DOI: 10.1016/j.bmcl.2011.01.062 .(b) Leijen, S.; Middleton, M. R.; Tresca, P.; Kraeber-Bodéré, F.; Dieras, V.; Scheulen, M. E.; Gupta, A.; Lopez-Valverde, V.; Xu, Z. X.; Rueger, R.; Tessier, J. J.; Shochat, E.; Blotner, S.; Naegelen, V. M.; Schellens, J. H.; Eberhardt, W. E. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin. Cancer Res. 2012, 18, 4794– 4805, DOI: 10.1158/1078-0432.CCR-12-0868[Crossref], [PubMed], [CAS], Google Scholar143bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ygsb%252FE&md5=ad4ba0b2d82d87158432fbd976fd536ePhase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid TumorsLeijen, Suzanne; Middleton, Mark R.; Tresca, Patricia; Kraeber-Bodere, Francoise; Dieras, Veronique; Scheulen, Max E.; Gupta, Avinash; Lopez-Valverde, Vanesa; Xu, Zhi-Xin; Rueger, Ruediger; Tessier, Jean J. L.; Shochat, Eliezer; Blotner, Steve; Naegelen, Valerie Meresse; Schellens, Jan H. M.; Eberhardt, Wilfried Ernst ErichClinical Cancer Research (2012), 18 (17), 4794-4805CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its max. tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-wk cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approx. 4 h. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clin. benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a redn. in fluorodeoxyglucose uptake by positron emission tomog. between baseline and day 15. Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794-805. ©2012 AACR.
- 144Ohren, J. F.; Chen, H.; Pavlovsky, A.; Whitehead, C.; Zhang, E.; Kuffa, P.; Yan, C.; McConnell, P.; Spessard, C.; Banotai, C.; Mueller, W. T.; Delaney, A.; Omer, C.; Sebolt-Leopold, J.; Dudley, D. T.; Leung, I. K.; Flamme, C.; Warmus, J.; Kaufman, M.; Barrett, S.; Tecle, H.; Hasemann, C. A. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 2004, 11, 1192– 1197, DOI: 10.1038/nsmb859[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVens7jM&md5=79ebbc2e3a9cdd3fbecb8bb35ea9dba3Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibitionOhren, Jeffrey F.; Chen, Huifen; Pavlovsky, Alexander; Whitehead, Christopher; Zhang, Erli; Kuffa, Peter; Yan, Chunhong; McConnell, Patrick; Spessard, Cindy; Banotai, Craig; Mueller, W. Thomas; Delaney, Amy; Omer, Charles; Sebolt-Leopold, Judith; Dudley, David T.; Leung, Iris K.; Flamme, Cathlin; Warmus, Joseph; Kaufman, Michael; Barrett, Stephen; Tecle, Haile; Hasemann, Charles A.Nature Structural & Molecular Biology (2004), 11 (12), 1192-1197CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)MEK1 and MEK2 kinases are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK MAP kinase (MAPK) signaling pathway. Approx. 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here, the authors present the x-ray crystal structures of human MEK1 and MEK2 kinases, each detd. as a ternary complex with MgATP and an inhibitor to a resoln. of 2.4 and 3.2 Å, resp. The structures revealed that MEK1 and MEK2 each had a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitors induced several conformational changes in the unphosphorylated MEK1 and MEK2 kinases that locked them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
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- 147(a) Nicolaou, I.; Zika, C.; Demopoulos, V. J. [1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a bioisostere of a carboxylic acid aldose reductase inhibitor. J. Med. Chem. 2004, 47, 2706– 2709, DOI: 10.1021/jm031060t .(b) Alexiou, P.; Demopoulos, V. J. A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity. J. Med. Chem. 2010, 53, 7756– 7766, DOI: 10.1021/jm101008m[ACS Full Text.
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- 154(a) Bégué, J.-P.; Bonnet-Delpon, D. Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives. ChemMedChem 2007, 2, 608– 624, DOI: 10.1002/cmdc.200600156[Crossref], [PubMed], [CAS], Google Scholar.154ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVGrurw%253D&md5=5caf9964669f5c3a54f1c250d187046aFluoroartemisinins: metabolically more stable antimalarial artemisinin derivativesBegue, Jean-Pierre; Bonnet-Delpon, DanieleChemMedChem (2007), 2 (5), 608-624CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This report is an overview on the design, prepn., and evaluation of metabolically stable artemisinins, using fluorine substitution. The chem. challenges encountered for the incorporation of fluorine-contg. elements and the prepn. of a large range of 10-trifluoromethyl artemisinin derivs. are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted. Preclin. data of lead compds., and evidence for their strong and prolonged antimalarial activity are presented.(b) Magueur, G.; Crousse, B.; Ourévitch, M.; Bonnet-Delpon, D.; Bégué, J.-P. Fluoro-artemisinins: when a gem-difluoroethylene replaces a carbonyl group. J. Fluorine Chem. 2006, 127, 637– 642, DOI: 10.1016/j.jfluchem.2005.12.013[Crossref], [CAS], Google Scholar154bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xksl2jsLY%253D&md5=842374feac786a3df37b48f55d21d776Fluoro-artemisinins: When a gem-difluoroethylene replaces a carbonyl groupMagueur, Guillaume; Crousse, Benoit; Ourevitch, Michele; Bonnet-Delpon, Daniele; Begue, Jean-PierreJournal of Fluorine Chemistry (2006), 127 (4-5), 637-642CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)Exo-gem-difluoromethylene-artemisinin (I) has been designed to mimic artemisinin. The classical Wittig olefination reaction applied to artemisinin failed. An alternative reaction involving the generation of an α-CF3 carbanion, from the corresponding bromide, allowed the access to the target compd. I, and could also be applied to the sugar series. The replacement of the carbonyl function by a difluoroethylene moiety resulted in a better antimalarial activity.
- 155(a) Tu, Y. Artemisinin- a gift from traditional Chinese medicine to the world (Nobel lecture). Angew. Chem., Int. Ed. 2016, 55, 10210– 10226, DOI: 10.1002/anie.201601967 .(b) Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.; Tracking Resistance to Artemisinin Collaboration Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 2014, 371, 411– 423, DOI: 10.1056/NEJMoa1314981[Crossref], [PubMed], [CAS], Google Scholar155bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1ers7jF&md5=bb2f2a4d554ba6a1f4c605868be43f6eSpread of artemisinin resistance in Plasmodium falciparum malariaAshley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.New England Journal of Medicine (2014), 371 (5), 411-423, 13 pp.CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)Background: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geog. extent of resistance is essential for planning containment and elimination strategies. Methods: Between May 2011 and Apr. 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kg of body wt. per day or 4 mg per kg, for 3 days, followed by a std. 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 h, and the parasite clearance half-lives were detd. Results: The median parasite clearance half-lives ranged from 1.9 h in the Democratic Republic of Congo to 7.0 h at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 h), strongly assocd. with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from Southern Vietnam to central Myanmar. The incidence of pre-treatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In Western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was assocd. with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Conclusions: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is assocd. with mutations in kelch13. Prolonged courses of artemisinin- based combination therapies are currently efficacious in areas where std. 3-day treatments are failing. (Funded by the U.K. Department of International Development and others).
- 156(a) Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.; Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D. M.; Verdoorn, T. A.; Bollini, S.; Vinitsky, A. 2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies. Org. Lett. 2001, 3, 3987– 3990, DOI: 10.1021/ol0166909[ACS Full Text.
], [CAS], Google Scholar156ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlKrtbs%253D&md5=1310c65ef4d6c86f4664654c554105f92-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural StudiesDubowchik, Gene M.; Vrudhula, Vivekananda M.; Dasgupta, Bireshwar; Ditta, Jonathan; Chen, Ti; Sheriff, Steven; Sipman, Karin; Witmer, Mark; Tredup, Jeffrey; Vyas, Dolatrai M.; Verdoorn, Todd A.; Bollini, Sagarika; Vinitsky, AlexanderOrganic Letters (2001), 3 (25), 3987-3990CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)2-Aryl-2,2-difluoroacetamido derivs. of proline and pipecolate esters I (X = F2, O, H2; Y = N, CH) and II (p = 1, 2; n = 2, 3; m = 0-3) are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 Ph ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.(b) Bollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A. High-throughput fluorescence polarization method for identification of FKBP12 ligands. J. Biomol. Screening 2002, 7, 526– 530, DOI: 10.1177/1087057102238626[Crossref], [PubMed], [CAS], Google Scholar156bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFemt7c%253D&md5=2bea4698dfb7153e0d2ef0eae4c637a5High-throughput fluorescence polarization method for identification of FKBP12 ligandsBollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A.Journal of Biomolecular Screening (2002), 7 (6), 526-530CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)FKBP12 is best known as the target of the widely used immunosuppressive drug FK506 but may also play a role in neuronal survival. Nonimmunosuppressive ligands of FKBP12 have been shown to have neuroprotective and neuroregenerative activity both in vitro and in vivo, stimulating interest in the development of high-throughput screens to rapidly identify novel ligands. FKBP12 was expressed as a His6-fusion in bacteria and purified by metal ion affinity and gel filtration chromatog. A high-throughput fluorescence polarization assay was developed to identify novel ligands of FKBP12. Dissocn. const. values of known FKBP12 ligands measured by the new method agreed closely with Ki values obtained by assaying inhibition of the rotamase activity of the enzyme. The fluorescence polarization assay is rapid, robust, and inexpensive and does not generate radioactive waste. It is very well suited for high-throughput screening efforts. - 157Ye, X. M.; Konradi, A. W.; Smith, J.; Aubele, D. L.; Garofalo, A. W.; Marugg, J.; Neitzel, M. L.; Semko, C. M.; Sham, H. L.; Sun, M.; Truong, A. P.; Wu, J.; Zhang, H.; Goldbach, E.; Sauer, J.-M.; Brigham, E. F.; Bova, M.; Basi, G. S. Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II). Bioorg. Med. Chem. Lett. 2010, 20, 3502– 3506, DOI: 10.1016/j.bmcl.2010.04.148[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntVCmsLg%253D&md5=712a8056390ea9663f0af178abc94712Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)Ye, Xiaocong M.; Konradi, Andrei W.; Smith, Jenifer; Aubele, Danielle L.; Garofalo, Albert W.; Marugg, Jennifer; Neitzel, Marty L.; Semko, Chris M.; Sham, Hing L.; Sun, Minghua; Truong, Anh P.; Wu, Jing; Zhang, Hongbin; Goldbach, Erich; Sauer, John-Michael; Brigham, Elizabeth F.; Bova, Michael; Basi, Guriqbal S.Bioorganic & Medicinal Chemistry Letters (2010), 20 (12), 3502-3506CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
- 158Xiamuxi, H.; Wang, Z.; Li, J.; Wang, Y.; Wu, C.; Yang, F.; Jiang, X.; Liu, Y.; Zhao, Q.; Chen, W.; Zhang, J.; Xie, Y.; Hu, T.; Xu, M.; Guo, S.; Akber Aisa, H.; He, Y.; Shen, J. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multi-receptor atypical antipsychotics. Bioorg. Med. Chem. 2017, 25, 4904– 4916, DOI: 10.1016/j.bmc.2017.07.040
- 159(a) Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J. Chem. 2004, 28, 1401– 1411, DOI: 10.1039/b405955g[Crossref], [CAS], Google Scholar.159ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVGqur3P&md5=7f40c026008b7e521e5a8d47cdc6c36cTrifluoromethyl group: an effective xenobiotic function for peptide backbone modificationZanda, MatteoNew Journal of Chemistry (2004), 28 (12), 1401-1411CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)A review. Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in the solid phase, for many different fluoroalkyl peptidomimetics, i.e., bis-trifluoromethyl (Tfm) analogs of Pepstatin A, which are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II; Tfm-malic peptidomimetics that are micromolar inhibitors of some matrix metalloproteinases; partially modified retro (PMR) and retro-inverso (PMRI) ψ[CH(CF3)NH] peptides with a strong proclivity to assume turn-like conformations; ψ[CH(CF3)NH] peptide mimics having a great potential as hybrids between natural peptides and hydrolytic transition state analogs; PMR peptides incorporating a trifluoroalanine surrogate. These novel classes of fluorinated peptide mimics are likely to represent just the tip of an iceberg formed by new peptidomimetic structures with unique biomedicinal and pharmaceutical properties.(b) Sani, M.; Volonterio, A.; Zanda, M. The trifluoroethylamine function as peptide bond replacement. ChemMedChem 2007, 2, 1693– 1700, DOI: 10.1002/cmdc.200700156[Crossref], [PubMed], [CAS], Google Scholar.159bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltlWlt7c%253D&md5=f319f5ec15482837b159ae6776302717The trifluoroethylamine function as peptide bond replacementSani, Monica; Volonterio, Alessandro; Zanda, MatteoChemMedChem (2007), 2 (12), 1693-1700CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Synthesis of peptidomimetics contg. a stereogenic trifluoroethylamine group in place of the peptide bond is discussed. Peptidomimetics contg. the trifluoroethylamine group in place of amide group have been found to be highly potent and metabolically stable inhibitors of cathepsin K.(c) Brusoe, A. T.; Hartwig, J. F. Palladium-catalyzed arylation of fluoroalkylamines. J. Am. Chem. Soc. 2015, 137, 8460– 8468, DOI: 10.1021/jacs.5b02512[ACS Full Text
], [CAS], Google Scholar159chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansrvF&md5=635a13908c88a8d23fb350d2ba6584bePalladium-Catalyzed Arylation of FluoroalkylaminesBrusoe, Andrew T.; Hartwig, John F.Journal of the American Chemical Society (2015), 137 (26), 8460-8468CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We report the synthesis of fluorinated anilines by palladium-catalyzed coupling of fluoroalkylamines with aryl bromides and aryl chlorides. The products of these reactions are valuable because anilines typically require the presence of an electron-withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidn., and the fluoroalkyl groups have steric properties and polarity distinct from those of more common electron-withdrawing amide and sulfonamide units. The fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base). However, the reactions conducted with the weaker base KOPh, which has rarely been used in cross-coupling to form C-N bonds, occurred in high yields in the presence of a catalyst derived from com. available AdBippyPhos and [Pd(allyl)Cl]2. Under these conditions, the reactions occur with low catalyst loadings (<0.50 mol % for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross-coupling reactions of aryl halides. The resting state of the catalyst is the phenoxide complex, [BippyPhosPd(Ar)OPh]; due to the electron-withdrawing property of the fluoroalkyl substituent, the turnover-limiting step of the reaction is reductive elimination to form the C-N bond. - 160(a) Volonterio, A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.; Bruche, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille, S. V.; Meli, M.; Ramirez de Arellano, C.; Zanda, M. Synthesis, structure and conformation of partially-modified retro- and retro-inverso Ψ[NHCH(CF3)]Gly peptides. Chem. - Eur. J. 2003, 9, 4510– 4522, DOI: 10.1002/chem.200304881[Crossref], [PubMed], [CAS], Google Scholar.160ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVygtb0%253D&md5=cba456e90602f8c832d751c3845db257Synthesis, structure and conformation of partially-modified retro- and retro-inverso ψ[NHCH(CF3)]Gly peptidesVolonterio, Alessandro; Bellosta, Stefano; Bravin, Fabio; Bellucci, Maria Cristina; Bruche, Luca; Colombo, Giorgio; Malpezzi, Luciana; Mazzini, Stefania; Meille, Stefano V.; Meli, Massimiliano; Ramirez de Arellano, Carmen; Zanda, MatteoChemistry - A European Journal (2003), 9 (18), 4510-4522CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Partially modified retro- (PMR) and retro-inverso (PMRI) ψ[NHCH(CF3)]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure α-amino esters and peptides with enantiomerically and geometrically pure N-(4,4,4-trifluorocrotonoyl)oxazolidin-2-ones. The factors underlying the obsd. moderate to good diastereocontrol have been investigated. The conformations of model PMR-ψ[NHCH(CF3)]Gly tripeptides have been studied in soln. by 1H NMR spectroscopy supported by MD calcns., as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: (1) severe torsional restrictions about sp3 bonds in the [CO-CH2-CH(CF3)-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF3 group and the R side chain and (2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl3 soln. and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramol. hydrogen bonding. The relative configuration of the -C*H(CF3)NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochem. X-ray diffraction and ab initio computational studies showed that the [-CH(CF3)NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analog, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF3)-NH-CH backbone angle close to 120°, C-CF3 bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O-)NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron d. on the CF3 group, tetrahedral backbone carbon).(b) Molteni, M.; Pesenti, C.; Sani, M.; Volonterio, A.; Zanda, M. Fluorinated peptidomimetics: synthesis, conformational and biological features. J. Fluorine Chem. 2004, 125, 1735– 1743, DOI: 10.1016/j.jfluchem.2004.09.014[Crossref], [CAS], Google Scholar.160bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVKrsbzP&md5=cb3388b61377efa640f6788c60df7109Fluorinated peptidomimetics: synthesis, conformational and biological featuresMolteni, Marco; Pesenti, Cristina; Sani, Monica; Volonterio, Alessandro; Zanda, MatteoJournal of Fluorine Chemistry (2004), 125 (11), 1735-1743CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Our interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in solid phase, for many different fluoroalkyl peptidomimetics, some of which are overviewed in this paper: (a) ψ[CH(CF3)NH]-peptide mimics holding a great potential as hybrids between natural peptides and hydrolytic transition state analogs, (b) trifluoromethyl (Tfm) malic peptidomimetics as micromolar inhibitors of some matrix metalloproteinases, and (c) bis-Tfm analogs of pepstatin A, that are nanomolar and selective inhibitors of the protozoal aspartyl protease plasmepsin II.(c) Molteni, M.; Bellucci, M. C.; Bigotti, S.; Mazzini, S.; Volonterio, A.; Zanda, M. Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysis. Org. Biomol. Chem. 2009, 7, 2286– 2296, DOI: 10.1039/b901718f[Crossref], [PubMed], [CAS], Google Scholar160chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFKntrc%253D&md5=d7b00a73b1409503bead497218549024Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysisMolteni, Marco; Bellucci, Maria Cristina; Bigotti, Serena; Mazzini, Stefania; Volonterio, Alessandro; Zanda, MatteoOrganic & Biomolecular Chemistry (2009), 7 (11), 2286-2296CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Ψ[CH(CF3)NH]Gly peptides, a conceptually new class of peptidomimetics having a stereogenic trifluoroethylamine group as a natural peptide-bond surrogate, have been synthesized by aza-Michael stereoselective addn. of α-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. Long range nuclear Overhauser effects, detected via ROESY expts., provided evidence that model Ψ[CH(CF3)NH]Gly-tetrapeptides incorporating a trifluoroethylamine mimic of the dipeptide loop Pro-Gly can be represented by an ensemble of unfolded and folded conformations. The latter are driven by the formation of a hydrogen bond between a carbonyl group and the aminic proton of the trifluoroethylamine unit. MD calcns. indicate a population of conformers which adopt folded β turn structures for all the L-peptides; on the other hand, a D-stereochem. at the Pro residue induces a natural folding towards a β hairpin conformation driven by the formation of a second hydrogen bond, regardless of the stereochem. of the stereogenic peptide bond surrogate.
- 161(a) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Leger, S.; Li, C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741– 4744, DOI: 10.1016/j.bmcl.2005.07.071[Crossref], [PubMed], [CAS], Google Scholar.161ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVanu7%252FE&md5=c2ffc9bde9fbee7bb432d3c2485cfc62Trifluoroethylamines as amide isosteres in inhibitors of cathepsin KBlack, W. Cameron; Bayly, Christopher I.; Davis, Dana E.; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Leger, Serge; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Palmer, James T.; Percival, M. David; Robichaud, Joel; Tsou, Nancy; Zamboni, RobertBioorganic & Medicinal Chemistry Letters (2005), 15 (21), 4741-4744CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The nonbasic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compds. are 10- to 20-fold more potent than the corresponding amide derivs. Compd. (I) is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.(b) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Thérien, M.; Truong, V.-L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985– 1989, DOI: 10.1016/j.bmcl.2005.12.071[Crossref], [PubMed], [CAS], Google Scholar.161bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvVyqs74%253D&md5=e63e471204893774e5a617993ed9be18Identification of a potent and selective non-basic cathepsin K inhibitorLi, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald. B.; Leger, Serge; Masse, Frederic; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Therien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2006), 16 (7), 1985-1989CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of L-873724 (I) as a potent and selective non-basic cathepsin K inhibitor. This compd. showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The vols. of distribution close to unity were consistent with this compd. not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.(c) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.T.; Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923– 928, DOI: 10.1016/j.bmcl.2007.12.047[Crossref], [PubMed], [CAS], Google Scholar.161chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktro%253D&md5=e432a420a3ec99c784117750b9bbeda8The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin KGauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean-Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Leger, Serge; LeRiche, Tammy; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Nicoll-Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Joel; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Therien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2008), 18 (3), 923-928CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclin. species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.(d) Mullard, A. Merck & Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discovery 2016, 15, 669, DOI: 10.1038/nrd.2016.207[Crossref], [CAS], Google Scholar161dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFymtL3M&md5=596d89f78b8396f0193a4ecfaf6b50bdMerck & Co. drops osteoporosis drug odanacatibMullard, AsherNature Reviews Drug Discovery (2016), 15 (10), 669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A discussion of the osteoporosis drug odanacatib.
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- 163Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M.-H.; Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B. T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. Aminomethyl-derived beta secretase (BACE-1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem. 2017, 60, 386– 402, DOI: 10.1021/acs.jmedchem.6b01451
- 164(a) Chen, G.; Ren, H.; Turpoff, A.; Arefolov, A.; Wilde, R.; Takasugi, J.; Khan, A.; Almstead, N.; Gu, Z.; Komatsu, T.; Freund, C.; Breslin, J.; Colacino, J.; Hedrick, J.; Weetall, M.; Karp, G. M. Discovery of N-(4′-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication. Bioorg. Med. Chem. Lett. 2013, 23, 3942– 3946, DOI: 10.1016/j.bmcl.2013.04.050 .(b) Zhang, X.; Zhang, N.; Chen, G.; Turpoff, A.; Ren, H.; Takasugi, J.; Morrill, C.; Zhu, J.; Li, C.; Lennox, W.; Paget, S.; Liu, Y.; Almstead, N.; Njoroge, F. G.; Gu, Z.; Komatsu, T.; Clausen, V.; Espiritu, C.; Graci, J.; Colacino, J.; Lahser, F.; Risher, N.; Weetall, M.; Nomeir, A.; Karp, G. M. Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. Bioorg. Med. Chem. Lett. 2013, 23, 3947– 3953, DOI: 10.1016/j.bmcl.2013.04.049[Crossref], [PubMed], [CAS], Google Scholar.164bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSisrw%253D&md5=c4ea419ba26dea48358a3036caf48abfDiscovery of novel HCV inhibitors: Synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4BZhang, Xiaoyan; Zhang, Nanjing; Chen, Guangming; Turpoff, Anthony; Ren, Hongyu; Takasugi, James; Morrill, Christie; Zhu, Jin; Li, Chunshi; Lennox, William; Paget, Steven; Liu, Yalei; Almstead, Neil; George Njoroge, F.; Gu, Zhengxian; Komatsu, Takashi; Clausen, Valerie; Espiritu, Christine; Graci, Jason; Colacino, Joseph; Lahser, Fred; Risher, Nicole; Weetall, Marla; Nomeir, Amin; Karp, Gary M.Bioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3947-3953CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides I [R1 = CHF2O, c-Pr; R2 = i-Pr, H, CH(CH2F)2, etc.] was prepd. and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compds. with low nanomolar potency against the HCV genotype 1b replicon. Among these, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] was identified as a potent HCV replicon inhibitor (EC50 = 4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] had a good pharmacokinetic profile in rats with an IV half-life of 6 h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compds. These compds. hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.(c) Zhang, N.; Zhang, X.; Zhu, J.; Turpoff, A.; Chen, G.; Morrill, C.; Huang, S.; Lennox, W.; Kakarla, R.; Liu, R.; Li, C.; Ren, H.; Almstead, N.; Venkatraman, S.; Njoroge, F. G.; Gu, Z.; Clausen, V.; Graci, J.; Jung, S. P.; Zheng, Y.; Colacino, J. M.; Lahser, F.; Sheedy, J.; Mollin, A.; Weetall, M.; Nomeir, A.; Karp, G.M. Structure–activity relationship (SAR) optimization of 6-(indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B. J. Med. Chem. 2014, 57, 2121– 2135, DOI: 10.1021/jm401621g
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- 166Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Hiner, R. N.; Dorsey, G. F.; Noe, R. A.; Unwalla, R. J.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; van Arnold, J.; Bickett, D. M.; Moss, M. L.; Tian, G.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Croom, D. K. Structure-activity relationships for inhibition of type 1 and 2 human 5α-reductase and human adrenal 3β-hydroxy-Δ5-steroid dehydrogenase/3-keto-Δ5-steroid isomerase by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent. J. Med. Chem. 1995, 38, 2621– 2627, DOI: 10.1021/jm00014a015
- 167(a) di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A. Novel aromatase and 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol. 1994, 49, 289– 294, DOI: 10.1016/0960-0760(94)90270-4[Crossref], [PubMed], [CAS], Google Scholar.167ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlvFKhs7w%253D&md5=9575b614af25a96aaddeeedfdc695ce1Novel aromatase and 5α-reductase inhibitorsDi Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A.Journal of Steroid Biochemistry and Molecular Biology (1994), 49 (4-6), 289-94CODEN: JSBBEZ; ISSN:0960-0760.Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, resp. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compd. was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compd. was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17β-amidic side chains, three compds., namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5α-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, resp. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compds. were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, resp.(b) Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Ihelè, C.; Nesi, M.; Panzeri, A.; di Salle, E. FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effects. J. Steroid Biochem. Mol. Biol. 1996, 58, 299– 305, DOI: 10.1016/0960-0760(96)00040-4[Crossref], [PubMed], [CAS], Google Scholar.167bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmtFWlurY%253D&md5=d67d010818dd73d38f1b7f4f4ded9465FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effectsGiudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Iehle, C.; Nesi, M.; Panzeri, A.; di Salle, E.Journal of Steroid Biochemistry and Molecular Biology (1996), 58 (3), 299-305CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier)FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compd. causes inhibition of rat and human prostatic enzymes, with IC50 values of 15 an d16 nM, resp., compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isoenzymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isoenzymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult rats, FCE 28260 reduced prostatic DHT concns. 6 h after oral dosing with a potency similar to that of finasteride (65% redn. at 1 mg/kg) but was found to be markedly more potent than the ref. compd. at 24 h (74% redn. in prostate DHT at 10 mg/kg, compared to 26% redn. induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.(c) di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Délos, S.; Martin, P. M. PNU 157706, a novel dual type I and II 5α-reductase inhibitor. J. Steroid Biochem. Mol. Biol. 1998, 64, 179– 186, DOI: 10.1016/S0960-0760(97)00158-1[Crossref], [PubMed], [CAS], Google Scholar.167chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1Siur4%253D&md5=05e5f3843393d77fc18cdb04017eaf76PNU 157706, a novel dual type I and II 5α-reductase inhibitorDi Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Delos, S.; Martin, P. M.Journal of Steroid Biochemistry and Molecular Biology (1998), 64 (3-4), 179-186CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Science Ltd.)PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). Tested on a crude prepn. of human or rat prostatic 5α-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, resp., compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5α-R type I and II isoenzymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isoenzyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting redn. of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, resp.). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate wt. in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate wt., the ED50 values being 0.12 and 1.9 mg/kg/day, resp. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5α-R with a very marked antiprostatic effect in the rat.(d) Basileo, G.; Breda, M.; James, C. A. Determination of PNU-157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection. J. Chromatogr., Biomed. Appl. 1998, 719, 191– 197, DOI: 10.1016/S0378-4347(98)00412-5[Crossref], [PubMed], [CAS], Google Scholar167dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXotFajs7s%253D&md5=badecb35cf011122235d7c7c89aabb12Determination of PNU 157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detectionBasileo, G.; Breda, M.; James, C. A.Journal of Chromatography B: Biomedical Sciences and Applications (1998), 719 (1 + 2), 191-197CODEN: JCBBEP; ISSN:0378-4347. (Elsevier Science B.V.)A HPLC procedure was developed and validated for detg. nanogram per mL concns. of the dual 5a-reductase inhibitor PNU 157706 in rat plasma. The compd. was extd. from plasma with di-Et ether followed by purifn. on a CN cartridge. The chromatog. sepn. was performed on a C18 column with water-acetonitrile-methanol mixt. as eluent. UV detection at 210 nm was used for the quantification of the compd. over the concn. range 5-500 ng/mL plasma. The method has a lower limit of quantification of 5 ng/mL and good precision and accuracy. This method performed well during anal. of several toxicokinetic and pharmacokinetic studies in the rat.
- 168(a) Drury, J. E.; Di Costanzo, L.; Penning, T. M.; Christianson, D. W. Inhibition of human steroid 5α-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex. J. Biol. Chem. 2009, 284, 19786– 19790, DOI: 10.1074/jbc.C109.016931 .(b) Karnsomwan, W.; Rungrotmongkol, T.; De-Eknamkul, W.; Chamni, S. chamni, S. In silico prediction of human steroid 5α-reductase type II. Med. Chem. Res. 2016, 25, 1049– 1056, DOI: 10.1007/s00044-016-1541-y[Crossref], [CAS], Google Scholar168bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVamtL0%253D&md5=5859de732a06e99fb1587ebedb250d34In silico structural prediction of human steroid 5α-reductase type IIKarnsomwan, Wiranpat; Rungrotmongkol, Thanyada; De-Eknamkul, Wanchai; Chamni, SupakarnMedicinal Chemistry Research (2016), 25 (6), 1049-1056CODEN: MCREEB; ISSN:1054-2523. (Springer)Steroid 5α-reductase type II is a membrane-assocd. enzyme in an oxidoreductase family. This enzyme, which is found in male sexual organs, plays the important biol. actions toward steroid metab. Overexpression of 5α-reductase type II has affected the balance between testosterone and dihydrotestosterone, which implicates the androgenic disorders, including prostate cancer, hirsutism, and androgenic alopecia. Lack of single-crystal X-ray structures of 5α-reductase has hindered mechanistic understanding and delayed the discovery and development of an effective inhibitor. Herein, we illustrated a comparative structure of 5α-reductase type II that derived from the homol. modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template. A catalytic pocket and the transmembrane site were identified. The resulting in silico structure was validated via Ramachandran plot and confirmed by docking studies of 30 known 5α-reductase type I and type II inhibitors, including finasteride and dutasteride. The comparative docking study of the derived in silico 5α-reductase type II and 5β-reductase, a reported surrogate enzyme, was conducted. Our homol. model approx. fitted to the membrane-assocd. character and showed the reasonable docking results, which depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.
- 169(a) Howbert, J. J.; Grossman, C. S.; Crowell, T. A.; Rieder, B. J.; Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikins, J.; Poore, G. A. Novel agents effective against solid tumors: the diarylsulfonylureas. Synthesis, activities, and analysis of quantitative structure-activity relationships. J. Med. Chem. 1990, 33, 2393– 2407, DOI: 10.1021/jm00171a013 .(b) Mohamadi, F.; Spees, M. M.; Grindey, G. B. Sulfonylureas: a new class of cancer chemotherapeutic agents. J. Med. Chem. 1992, 35, 3012– 3016, DOI: 10.1021/jm00094a013
- 170(a) Houghton, P. J.; Houghton, J. A. Antitumor diarylsulfonylureas: novel agents with unfulfilled promise. Invest. New Drugs 1996, 14, 271– 280, DOI: 10.1007/BF00194530 .(b) Owa, T.; Nagasu, T. Novel sulphonamide derivatives for the treatment of cancer. Expert Opin. Ther. Pat. 2000, 10, 1725– 1740, DOI: 10.1517/13543776.10.11.1725[Crossref], [CAS], Google Scholar.170bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXnvF2gtb4%253D&md5=b30657724dc8b8ab4a50f733df0aa6f6Novel sulphonamide derivatives for the treatment of cancerOwa, Takashi; Nagasu, TakeshiExpert Opinion on Therapeutic Patents (2000), 10 (11), 1725-1740CODEN: EOTPEG; ISSN:1354-3776. (Ashley Publications Ltd.)A review with 265 refs. is given. The sulfonamides constitute an important class of therapeutic agents in current medicinal science. After the discovery by Gerhard Domagk, of sulphamidochrysoidine (prontosil) as the first antibiotic sulfa-drug an active metabolite of the drug, sulphanilamide, was further derivatized in order to find compds. exhibiting superior antibacterial activity or different pharmacol. effects. Diversification of the sulphanilamide structure led to the serial development of improved antibiotics, insulin-releasing hypoglycemic drugs, carbonic anhydrase- (CA) inhibitory diuretics, anti-hypertensive drugs etc. It is of particular interest that various structurally novel sulfonamide derivs. have recently been reported to show substantial anti-tumor activity in vitro and/or in vivo. Although they have a common chem. motif of an arom./heterocyclic sulfonamide, there are a variety of mechanisms for their anti-tumor action, such as disruption of microtubule assembly, cell cycle arrest in the G1 phase, functional suppression of the transcriptional activator NF-Y, angiogenesis inhibition and carbonic anhydrase inhibition. Furthermore, some of these compds. selected via elaborate preclin. screenings are currently being evaluated in clin. trials. This review summarizes recent patents and related papers which have disclosed novel classes of sulfonamide derivs. for the treatment of cancer.(c) Pasello, G.; Urso, L.; Conte, P.; Favaretto, A. Effects of sulfonylureas on tumor growth: a review of the literature. Oncologist 2013, 18, 1118– 1125, DOI: 10.1634/theoncologist.2013-0177
- 171Forouzesh, B.; Takimoto, C. H.; Goetz, A.; Diab, S.; Hammond, L. A.; Smetzer, L.; Schwartz, G.; Gazak, R.; Callaghan, J. T.; Von Hoff, D. D.; Rowinsky, E. K. A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies. Clin. Cancer Res. 2003, 9, 5540– 5549[PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpsVejtb4%253D&md5=2a6fc397223a4b0a24ee63d73723f1a6A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignanciesForouzesh, Bahram; Takimoto, Chris H.; Goetz, Andrew; Diab, Sami; Hammond, Lisa A.; Smetzer, Leslie; Schwartz, Garry; Gazak, Robert; Callaghan, John T.; Von Hoff, Daniel D.; Rowinsky, Eric K.Clinical Cancer Research (2003), 9 (15), 5540-5549CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 wk every 4-wk schedule. The study also sought to det. the max. tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. The initial starting dose of ILX-295501 was 100 mg/m2, which was equiv. to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m2. Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m2; and a modified continual reassessment model was used for dose assignment to det. the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m2. The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m2, which was detd. to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clin. relevant levels of oxidized Hb (metHb) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concns. (Cmax) achieving 6.02 h, on av., after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent vol. of distribution at steady state (Vss/F), averaging 8.02 ± 14.08 L, and low apparent total body clearance (CLt/F) rate (mean, 0.036 ± 0.116 L/h). The initial drug distribution phase was rapid [harmonic mean half-life (t1/2α), 2.1±7.0 min], whereas the terminal elimination phase was slow (harmonic mean t1/2β, 150.6 ± 80.2 h). The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 wk every 4 wk is 1000 mg/m2/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematol. toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.
- 172(a) Toth, J. E.; Grindey, G. B.; Ehlhardt, W. J.; Ray, J. E.; Boder, G. B.; Bewley, J. R.; Klingerman, K. K.; Gates, S. B.; Rinzel, S. M.; Schultz, R. M.; Weir, L. C.; Worzalla, J. F. Sulfonimidamide analogs of oncolytic sulfonylureas. J. Med. Chem. 1997, 40, 1018– 1025, DOI: 10.1021/jm960673l[ACS Full Text.
], [CAS], Google Scholar172ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhvVKqtLs%253D&md5=8020a75bb8a7b941d754d8a5d6e3aa9cSulfonimidamide Analogs of Oncolytic SulfonylureasToth, John E.; Grindey, Gerald B.; Ehlhardt, William J.; Ray, James E.; Boder, George B.; Bewley, Jesse R.; Klingerman, Kim K.; Gates, Susan B.; Rinzel, Sharon M.; Schultz, Richard M.; Weir, Leonard C.; Worzalla, John F.Journal of Medicinal Chemistry (1997), 40 (6), 1018-1025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for in vitro cytotoxicity against CEM cells, in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and metabolic breakdown to the o-sulfate of p-chloroaniline. The sepd. enantiomers of 1 sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or i.p. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.(b) Chern, J. W.; Leu, Y. L.; Wang, S. S.; Jou, R.; Lee, C. F.; Tsou, P. C.; Hsu, S. C.; Liaw, Y. C.; Lin, H. M. Synthesis and cytotoxic evaluation of substituted sulfonyl-N-hydroxyguanidine derivatives as potential antitumor agents. J. Med. Chem. 1997, 40, 2276– 2286, DOI: 10.1021/jm9607818 - 173(a) Luzina, E. L.; Popov, A. V. Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N′-thiazolyl and N-bis(trifluoromethyl)alkyl-N′-benzothiazolyl ureas. Eur. J. Med. Chem. 2009, 44, 4944– 4953, DOI: 10.1016/j.ejmech.2009.08.007 .(b) Luzina, E. L.; Popov, A. V. Anticancer activity of N-bis(trifluoromethyl)alkyl-N′-(polychlorophenyl) and N′-(1,2,4-triazolyl) ureas. Eur. J. Med. Chem. 2010, 45, 5507– 5512, DOI: 10.1016/j.ejmech.2010.08.057 .(c) Luzina, E. L.; Popov, A. V. Synthesis, evaluation of anticancer activity and COMPARE analysis of N-bis(trifluoromethyl)alkyl-N′-substituted ureas with pharmacophoric moieties. Eur. J. Med. Chem. 2012, 53, 364– 373, DOI: 10.1016/j.ejmech.2012.03.026
- 174Métayer, B.; Compain, G.; Jouvin, K.; Martin-Mingot, A.; Bachmann, C.; Marrot, J.; Evano, G.; Thibaudeau, S. Chemo- and stereo-selective synthesis of fluorinated enamides from ynamides in HF/pyridine: second-generation approach to potent ureas bioisosteres. J. Org. Chem. 2015, 80, 3397– 3410, DOI: 10.1021/jo502699y
- 175(a) Mewshaw, R. E.; Marquis, K. L.; Shi, X.; McGaughey, G.; Stack, G.; Webb, M. B.; Abou-Gharbia, M.; Wasik, T.; Scerni, R.; Spangler, T.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents 4. Exploiting the 2-methyl chroman scaffold. Synthesis and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano [2,3-e]indole and indol-8-one derivatives. Tetrahedron 1998, 54, 7081– 7108, DOI: 10.1016/S0040-4020(98)00349-4 .(b) Mewshaw, R. E.; Verwijs, A.; Shi, X.; McGaughey, G. B.; Nelson, j. A.; Mazandarani, H.; Brennan, J. A.; Marquis, K. L.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. 5. Heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template. Bioorg. Med. Chem. Lett. 1998, 8, 2675– 2680, DOI: 10.1016/S0960-894X(98)00474-0[Crossref], [PubMed], [CAS], Google Scholar.175bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntV2kt7s%253D&md5=e57316b9156bfe85ea046b9dd7b4eec5New generation dopaminergic agents. 5. heterocyclic bioisosteres that exploit the 3-OH-N'-phenylpiperazine dopaminergic templateMewshaw, Richard E.; Verwijs, Antoine; Shi, Xiaojie; Mcgaughey, Georgia B.; Nelson, James A.; Mazandarani, Hossein; Brennan, Julie A.; Marquis, Karen L.; Coupet, Joseph; Andree, Terrance H.Bioorganic & Medicinal Chemistry Letters (1998), 8 (19), 2675-2680CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis of several bioisosteric analogs based on the 3-OH-N'-phenylpiperazine dopamine D2 agonist template is described. The indolone (I) and 2-CF3-benzimidazole (II) were obsd. to have excellent affinity for the D2 receptor. Several D4 selective compds. were also identified. Mol. modeling studies and a putative bioactive conformation are discussed.(c) Mewshaw, R. E.; Nelson, J. A.; Shah, U. S.; Shi, X.; Mazandarani, H.; Coupet, J.; Marquis, K.; Brennan, J. A.; Andree, T. H. New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template. Bioorg. Med. Chem. Lett. 1999, 9, 2593– 2598, DOI: 10.1016/S0960-894X(99)00434-5 .(d) Mewshaw, R. E.; Zhao, R.; Shi, X.; Marquis, K.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. Part 8: heterocyclic bioisosteres that exploit the 7-OH-2-(aminomethyl)chroman D2 template. Bioorg. Med. Chem. Lett. 2002, 12, 271– 274, DOI: 10.1016/S0960-894X(01)00778-8
- 176Banks, J. W.; Batsanov, A. S.; Howard, J. A. K.; O’Hagan, D.; Rzepa, H. S.; Martin-Santamaria, S. The preferred conformation of α-fluoroamides. J. Chem. Soc., Perkin Trans. 2 1999, 2409– 2411, DOI: 10.1039/a907452j[Crossref], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmvFyku70%253D&md5=2f07b92ce6ca5799dbb3017f2a67263fThe preferred conformation of α-fluoroamidesBanks, John W.; Batsanov, Andrei S.; Howard, Judith A. K.; O'Hagan, David; Rzepa, Henry S.; Martin-Santamaria, SonsolesJournal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1999), (11), 2409-2411CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)X-Ray structures of two α-fluoroamide derivs. show the O:C-C-F moiety tending towards a trans planar conformation, for which ab initio calcns. suggest a deep (up to 8 kcal mol-1) potential min.
- 177Olivato, P. R.; Guerrero, S. A.; Yreijo, M. H.; Rittner, R.; Tormena, C. F. Conformational and electronic interaction studies of 2-fluoro-substituted N,N-dimethylamides. J. Mol. Struct. 2002, 607, 87– 99, DOI: 10.1016/S0022-2860(01)00761-X
- 178Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. The C-F bond as a tool in the conformational control of amides. J. Fluorine Chem. 2003, 119, 9– 13, DOI: 10.1016/S0022-1139(02)00243-9[Crossref], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsVektLs%253D&md5=1654f99734ae8bc262c6409d13382ff5The C-F bond as a tool in the conformational control of amidesBriggs, Caroline R. S.; O'Hagan, David; Howard, Judith A. K.; Yufit, Dmitrii S.Journal of Fluorine Chemistry (2003), 119 (1), 9-13CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science B.V.)The conformation of 2-fluoro-N-(2-fluoroethyl)-propionamide 4 in the solid state indicates the influence of both a β-F-amide gauche effect and an α-fluoroamide effect. The structure reveals the influence of two recently obsd. stereoelectronic effects assoc. with the C-F bond, which resulted in the successful prediction of the solid state conformation of amide 4. A gauche relation (-69.9°) was obsd. for atoms N(1)-C(4)-C(5)-F and a syn planar (2.0°) relation was obsd. for N(1)-C(3)-C(2)-F. The paper demonstrates the predictive power of using the C-F bond as a tool in influencing the conformation of amides and peptides.
- 179Winkler, M.; Moraux, T.; Khairy, H. A.; Scott, R. H.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and vanilloid receptor (TRPV1) activity of the enantiomers of α-fluorinated capsaicin. ChemBioChem 2009, 10, 823– 828, DOI: 10.1002/cbic.200800709
- 180(a) Jones, C. R.; Baruah, P. K.; Thompson, A. L.; Scheiner, S.; Smith, M. D. Can. a C–H···O interaction be a determinant of conformation?. J. Am. Chem. Soc. 2012, 134, 12064– 12071, DOI: 10.1021/ja301318a .(b) Driver, R. W.; Claridge, T. D. W.; Scheiner, S.; Smith, M. D. Torsional and electronic factors control the C–H···O interaction. Chem. - Eur. J. 2016, 22, 16513– 16521, DOI: 10.1002/chem.201602905[Crossref], [PubMed], [CAS], Google Scholar.180bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1ejtrnO&md5=5d9c737d8b5a6e4604897d094fc02d18Torsional and Electronic Factors Control the C-H...O InteractionDriver, Russell W.; Claridge, Timothy D. W.; Scheiner, Steve; Smith, Martin D.Chemistry - A European Journal (2016), 22 (46), 16513-16521CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The precise role of nonconventional hydrogen bonds such as the C-H...O interaction in influencing the conformation of small mols. remains unresolved. Here the authors survey β-turn mimetics using x-ray crystallog. and NMR spectroscopy in conjunction with quantum calcn., and conclude that favorable torsional and electronic effects are important for the population of states with conformationally influential C-H...O interactions. Results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions to focus on the contribution of a single one. Within a small mol. that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chem. shift data are extremely challenging to rationalize.(c) Koeller, S.; Thomas, C.; Peruch, F.; Deffieux, A.; Massip, S.; Léger, J.-M.; Desvergne, J.-P.; Milet, A.; Bibal, B. α-Halogenoacetanilides as hydrogen-bonding organocatalysts that activate carbonyl bonds: fluorine versus chlorine and bromine. Chem. - Eur. J. 2014, 20, 2849– 2859, DOI: 10.1002/chem.201303662[Crossref], [PubMed], [CAS], Google Scholar.180chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFSnsrk%253D&md5=1a36d371373fec506a463a59036f103aα-Halogenoacetanilides as Hydrogen-Bonding Organocatalysts that Activate Carbonyl Bonds: Fluorine versus Chlorine and BromineKoeller, Sylvain; Thomas, Coralie; Peruch, Frederic; Deffieux, Alain; Massip, Stephane; Leger, Jean-Michel; Desvergne, Jean-Pierre; Milet, Anne; Bibal, BrigitteChemistry - A European Journal (2014), 20 (10), 2849-2859CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)α-Halogenoacetanilides (X = F, Cl, Br) with substituents on the Ph ring were examd. as H-bonding organocatalysts designed for the double activation of C=O bonds through NH and CH donor groups. Depending on the halide substituents, the double H-bond involved a nonconventional C···H···O interaction with either a H-CXn (n= 1-2, X = Cl, Br) or a H-CAr bond (X = F), as shown in the solid-state crystal structures and by mol. modeling. In addn., the catalytic properties of α-haloacetanilides were evaluated in the ring-opening polymn. of lactide, in the presence of a tertiary amine as cocatalyst. The α-dichloro- and α-dibromoacetanilides contg. electron-deficient arom. groups afforded the most attractive double H-bonding properties towards C=O bonds, with a N-H···O···H···CX2 interaction.(d) Jaun, B.; Seebach, D.; Mathad, R. I. Note: Helix or no helix of β-peptides containing β3hAla(αF) residues?. Helv. Chim. Acta 2011, 94, 355– 361, DOI: 10.1002/hlca.201100023 .(e) Chekhlov, A. N.; Aksinenko, A. Yu.; Pushin, A. N.; Sokolov, V. B. An unusually strong intramolecular C-H•••N hydrogen bond in 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine. Russ. Chem. Bull. 1995, 44, 1531– 1532, DOI: 10.1007/BF00714447 .(f) Chekhlov, A. N. Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine with an unusually short intramolecular C-H•••N hydrogen bond. Kristallografiya 1995, 842– 847[CAS], Google Scholar.180fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXos1OnsbY%253D&md5=2dfa2d9e428ef57caaa9565fd2b028b8Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-(α-hydroperfluoroisobutyryl)imino-1,3-thiazolidine with an unusually short intramolecular C-H···N hydrogen bondChekhlov, A. N.Kristallografiya (1995), 40 (5), 842-7CODEN: KRISAJ; ISSN:0023-4761. (MAIK Nauka)The title compd. is monoclinic, space group P21/n, with a 9.203(1), b 10.349(1), c 17.299(2) Å, and β 95.74(1)°; Z = 4, dc = 1.857; R = 0.059 for 2075 reflections. At. coordinates are given. The 5-membered thiazolidine ring has half-chair conformation. This mol. has an unusually short H bond C-H...N with H...N distance 2.00(3) Å. The mol. also has a significantly shortened contact S...O 2.652(2) Å, with nonvalent interaction between S and O atoms. In the crystal structure, the mols. are connected in centrosym. dimer pairs with intermol. H bonds of C-H...O type with H...O distance of 2.38(3) Å.(g) Brewitz, L.; Arteaga Arteaga, F.; Yin, L.; Alagiri, K.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric Mannich-type reaction of α- and β-fluorinated amides. J. Am. Chem. Soc. 2015, 137, 15929– 15939, DOI: 10.1021/jacs.5b11064[ACS Full Text.
], [CAS], Google Scholar180ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVanurfN&md5=47c9b3a6c40395ae00ea0e6e6e803f67Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated AmidesBrewitz, Lennart; Arteaga, Fernando Arteaga; Yin, Liang; Alagiri, Kaliyamoorthy; Kumagai, Naoya; Shibasaki, MasakatsuJournal of the American Chemical Society (2015), 137 (50), 15929-15939CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amts. of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivs. for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-contg. small mols., α- and β-fluorinated carbonyl compds. have been neglected in direct enolization chem. because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Bronsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chem.(h) Brewitz, L.; Noda, H.; Kumagai, N.; Shibasaki, M. Structural and computational investigation of intramolecular N•••H interactions in α- and β-fluorinated 7-azaindoline amides. Eur. J. Org. Chem. 2017, DOI: 10.1002/ejoc.201701083 - 181Jones, C. R.; Dan Pantos, G. D.; Morrison, A. J.; Smith, M. D. Plagiarizing proteins: enhancing efficiency in asymmetric hydrogen-bonding catalysis through positive cooperativity. Angew. Chem., Int. Ed. 2009, 48, 7391– 7394, DOI: 10.1002/anie.200903063[Crossref], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFGrs7%252FI&md5=719944fad5c7ebfca0ee752d774f3e32Plagiarizing Proteins: Enhancing Efficiency in Asymmetric Hydrogen-Bonding Catalysis through Positive CooperativityJones, Christopher R.; Dan Pantos, G.; Morrison, Angus J.; Smith, Martin D.Angewandte Chemie, International Edition (2009), 48 (40), 7391-7394, S7391/1-S7391/127CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A hairpin turn intramol. H-bonded thiourea-urea catalyst was proficient in the highly enantioselective Mukaiyama-Mannich reaction of arom. BOC-aldimines with silyl ketene acetal nucleophile, providing β-aryl β-amino acids in 97 to >99% ee. Deletion of the urea H-bond donor group revealed that the effect of conformational ordering on the asym. induction is significant but relatively small. The intramol. H-bonded catalyst out-competed the urea-deleted catalyst in a competition reaction, suggesting tighter ligand-receptor binding in the transition state and tighter noncovalent interactions in the former case, and also exhibited higher anion-binding ability - consistent with cooperative ligand binding.
- 182Unione, L.; Alcalá, M.; Echeverria, B.; Serna, S.; Ardá, A.; Franconetti, A.; Cañada, F. J.; Diercks, T.; Reichardt, N.; Jiménez-Barbero, J. Fluoroacetamide moieties as NMR spectroscopy probes for the molecular recognition of GlcNAc-containing sugars: modulation of the CH−π stacking interactions by different fluorination patterns. Chem. - Eur. J. 2017, 23, 3957– 3965, DOI: 10.1002/chem.201605573[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtlymsrY%253D&md5=91246ebe88bc77a9219ffb10695eae1dFluoroacetamide Moieties as NMR Spectroscopy Probes for the Molecular Recognition of GlcNAc-Containing Sugars: Modulation of the CH-π Stacking Interactions by Different Fluorination PatternsUnione, Luca; Alcala, Maria; Echeverria, Begona; Serna, Sonia; Arda, Ana; Franconetti, Antonio; Canada, F. Javier; Diercks, Tammo; Reichardt, Niels; Jimenez-Barbero, JesusChemistry - A European Journal (2017), 23 (16), 3957-3965CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)We herein propose the use of fluoroacetamide and difluoroacetamide moieties as sensitive tags for the detection of sugar-protein interactions by simple 1H and/or 19F NMR spectroscopy methods. In this process, we have chosen the binding of N,N'-diacetyl chitobiose, a ubiquitous disaccharide fragment in glycoproteins, by wheat-germ agglutinin (WGA), a model lectin. By using satn.-transfer difference (STD)-NMR spectroscopy, we exptl. demonstrate that, under soln. conditions, the mol. that contained the CHF2CONH- moiety is the stronger arom. binder, followed by the analog with the CH2FCONH- group and the natural mol. (with the CH3CONH- fragment). In contrast, the mol. with the CF3CONH- isoster displayed the weakest intermol. interaction (one order of magnitude weaker). Because sugar-arom. CH-π interactions are at the origin of these observations, these results further contribute to the characterization and exploration of these forces and offer an opportunity to use them to unravel complex recognition processes.
- 183(a) Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.; Adam, G.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J. Med. Chem. 1994, 37, 3231– 3239, DOI: 10.1021/jm00046a006[ACS Full Text.
], [CAS], Google Scholar183ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmsFGgur4%253D&md5=e49a9e7136e045b8ba131d3281fe7082Synthesis and Structure-Activity Relationships of Novel Naphthalenic and Bioisosteric Related Amidic Derivatives as Melatonin Receptor LigandsDepreux, Patrick; Lesieur, Daniel; Mansour, Hamid Ait; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; et al.Journal of Medicinal Chemistry (1994), 37 (20), 3231-9CODEN: JMCMAR; ISSN:0022-2623.A series of N-naphthylethyl amide derivs. were synthesized and evaluated as melatonin receptor ligands. The affinity of each compd. for the melatonin receptor was detd. by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent on the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analog was a poor ligand. N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, a selective ligand of the melatonin receptor and an agonist deriv., has been selected for clin. development.(b) Leclerc, V.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola-Lemaître, B.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. 1998, 6, 1875– 1887, DOI: 10.1016/S0968-0896(98)00147-3[Crossref], [PubMed], [CAS], Google Scholar.183bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntlOhtbs%253D&md5=6ed68fd9dbf928caa550601c70cb3200Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligandsLeclerc, Veronique; Fourmaintraux, Eric; Depreux, Patrick; Lesieur, Daniel; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola-Lemaitre, Beatrice; Andrieux, JeanBioorganic & Medicinal Chemistry (1998), 6 (10), 1875-1887CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogs of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n-Pr urea deriv. is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This mol., a Pr deriv., or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclin. development.(c) Ettaoussi, M.; Sabaouni, A.; Rami, M.; Boutin, J. A.; Delagrange, P.; Renard, P.; Spedding, M.; Caignard, D.-H.; Berthelot, P.; Yous, S. Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). Eur. J. Med. Chem. 2012, 49, 310– 323, DOI: 10.1016/j.ejmech.2012.01.027 .(d) Zlotos, D. P.; Riad, N. M.; Osman, M. B.; Dodda, B. R.; Witt-Enderby, P. A. Novel difluoroacetamide analogues of agomelatine and melatonin: probing the melatonin receptors for MT1 selectivity. MedChemComm 2015, 6, 1340– 1344, DOI: 10.1039/C5MD00190K - 184Qiu, X.-L.; Xu, X.-H.; Qing, F.-L. Recent advances in the synthesis of fluorinated nucleosides. Tetrahedron 2010, 66, 789– 843, DOI: 10.1016/j.tet.2009.11.001
- 185Noble, S.; Goa, K. L. Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 1997, 54, 447– 472, DOI: 10.2165/00003495-199754030-00009[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvFelt7c%253D&md5=2479ca53d998ad70275a54db2b212169Gemcitabine. A review of its pharmacology and clinical potential in non-small-cell lung cancer and pancreatic cancerNoble, Stuart; Goa, Karen L.Drugs (1997), 54 (3), 447-472CODEN: DRUGAY; ISSN:0012-6667. (Adis)A review with 119 refs. Gemcitabine is a deoxycytidine analog which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy. Gemcitabine monotherapy produced an objective tumor response in 18-26% of patients with advanced non-small-cell lung cancer (NSCLC) and appears to have efficacy similar to that of cisplatin plus etoposide. Objective response rates ranging 26-54% were recorded when gemcitabine was combined with cisplatin, and 1-yr survival duration after such treatment ranged 35-61%. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clin. trials. Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addn., direct costs assocd. with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options. The combination of gemcitabine plus cisplatin was assocd. with a lower cost-per-tumor response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness anal. In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clin. status. It also showed modest antitumor and palliative efficacy in patients refractory to fluorouracil. Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerability profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study. Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity assocd. with many other chemotherapy regimens. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and palliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognized.
- 186Hui, C. K.; Lau, G.K. K. Clevudine for the treatment of chronic hepatitis B virus infection. Expert Opin. Invest. Drugs 2005, 14, 1277– 1284, DOI: 10.1517/13543784.14.10.1277
- 187(a) Sofia, M. J.; Bao, S.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Micolochick Steur, H. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis c virus. J. Med. Chem. 2010, 53, 7202– 7218, DOI: 10.1021/jm100863x .(b) Appleby, T. C.; Perry, J. K.; Murakami, E.; Barauskas, O.; Feng, J.; Cho, A.; Fox, D., III; Wetmore, D. R.; McGrath, M. E.; Ray, A. S.; Sofia, M. J.; Swaminathan, S.; Edwards, T. E. Structural basis for RNA replication by the hepatitis C virus polymerase. Science 2015, 347, 771– 775, DOI: 10.1126/science.1259210[Crossref], [PubMed], [CAS], Google Scholar187bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlKktrk%253D&md5=aeebcacedf36a44ae80c972100c80c24Structural basis for RNA replication by the hepatitis C virus polymeraseAppleby, Todd C.; Perry, Jason K.; Murakami, Eisuke; Barauskas, Ona; Feng, Joy; Cho, Aesop; Fox, David, III; Wetmore, Diana R.; McGrath, Mary E.; Ray, Adrian S.; Sofia, Michael J.; Swaminathan, S.; Edwards, Thomas E.Science (Washington, DC, United States) (2015), 347 (6223), 771-775CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Nucleotide analog inhibitors have shown clin. success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by detg. crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our anal. revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A β loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clin. active metabolite formed by sofosbuvir, to elucidate key mol. interactions in the active site.
- 188Van Roey, P.; Salerno, J. M.; Chu, C.-K.; Schinazi, R. F. Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 3929– 3933, DOI: 10.1073/pnas.86.11.3929
- 189Gore, K. R.; Harikrishna, S.; Pradeepkumar, P. I. Influence of 2′-fluoro versus 2′-O-methyl substituent on the sugar puckering of 4′-C-aminomethyluridine. J. Org. Chem. 2013, 78, 9956– 9962, DOI: 10.1021/jo4012333
- 190Zeng, D.; Zhang, R.; Nie, Q.; Cao, L.; Shang, L.; Yin, Z. Discovery of 2′-α-C-methyl-2′-β-C-fluorouridine phosphoramidate prodrugs as inhibitors of hepatitis C virus. ACS Med. Chem. Lett. 2016, 7, 1197– 1201, DOI: 10.1021/acsmedchemlett.6b00270
- 191Pallan, P. S.; Prakash, T. P.; de Leon, A. R.; Egli, M. Limits of RNA 2′-OH mimicry by fluorine: crystal structure of bacillus halodurans RNase H bound to a 2′-FRNA:DNA hybrid. Biochemistry 2016, 55, 5321– 5325, DOI: 10.1021/acs.biochem.6b00849[ACS Full Text
], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyhsL%252FN&md5=2bc94b04210f229dbee2b2f60bed9155Limits of RNA 2'-OH mimicry by fluorine: Crystal structure of Bacillus halodurans RNase H bound to a 2'-FRNA:DNA hybridPallan, Pradeep S.; Prakash, Thazha P.; de Leon, Arnie R.; Egli, MartinBiochemistry (2016), 55 (38), 5321-5325CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)RNase H1 cleaves the RNA strand of RNA:DNA hybrids. Replacement of RNA 2'-OH groups by F (FRNA) is commonly used to stabilize aptamers and siRNAs. However, FRNA:DNA hybrids fail to elicit RNase H1 activity. The underlying reasons are unclear, as 2'-OH groups are not directly involved in cleavage. Here, the authors detd. the crystal structure of Bacillus halodurans RNase H1 bound to a FRNA:DNA hybrid. The structure pointed to dynamic (slippage of the FRNA:DNA hybrid relative to the enzyme), geometric (different curvatures of FRNA:DNA and RNA:DNA hybrids), and electronic reasons (Mg2+ absent from the active site of the FRNA:DNA complex) for the loss of RNase H1 activity. - 192(a) Hinderaker, M. P.; Raines, R. T. An electronic effect on protein structure. Protein Sci. 2003, 12, 1188– 1194, DOI: 10.1110/ps.0241903[Crossref], [PubMed], [CAS], Google Scholar.192ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktV2ls78%253D&md5=221803b3d17053ea4f4804ccf372e55aAn electronic effect on protein structureHinderaker, Matthew P.; Raines, Ronald T.Protein Science (2003), 12 (6), 1188-1194CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)The well-known preference of the peptide bond for the trans conformation has been attributed to steric effects. Here, we show that a proline residue with an N-formyl group (Hi-1-C'i-1=Oi-1), in which Hi-1 presents less steric hindrance than does Oi-1, likewise prefers a trans conformation. Thus, the preference of the peptide bond for the trans conformation cannot be explained by steric effects alone. Rather, an n → π* interaction between the oxygen of the peptide bond (Oi-1), and the subsequent carbonyl carbon in the polypeptide chain (C'i) also contributes to this preference. The Oi-1 and C'i distance and Oi-1···C'i=Oi angle are esp. favorable for such an n → π* interaction in a polyproline II helix. We propose that this electronic effect provides substantial stabilization to this and other elements of protein structure.(b) Horng, J.-C.; Raines, R. T. Stereoelectronic effects on polyproline conformation. Protein Sci. 2006, 15, 74– 83, DOI: 10.1110/ps.051779806[Crossref], [PubMed], [CAS], Google Scholar.192bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktlSrtw%253D%253D&md5=07024cb52046bd729b1e9da61eb9bbafStereoelectronic effects on polyproline conformationHorng, Jia-Cherng; Raines, Ronald T.Protein Science (2006), 15 (1), 74-83CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)The polyproline type II (PPII) helix is a prevalent conformation in both folded and unfolded proteins, and is known to play important roles in a wide variety of biol. processes. Polyproline itself can also form a type I (PPI) helix, which has a disparate conformation. Here, we use derivs. of polyproline, (Pro)10, (Hyp)10, (Flp)10, and (flp)10, where Hyp is (2S,4R)-4-hydroxyproline, Flp is (2S,4R)-4-fluoroproline, and flp is (2S,4S)-4-fluoroproline, to probe for a stereoelectronic effect on the conformation of polyproline. CD spectral analyses show that 4R electron-withdrawing substituents stabilize a PPII helix relative to a PPI helix, even in a solvent that favors the PPI conformation, such as n-propanol. The stereochem. at C4 ordains the relative stability of PPI and PPII helixes, as (flp)10 forms a mixt. of PPI and PPII helixes in water and a PPI helix in n-propanol. The conformational preferences of (Pro)10 are intermediate between those of (Hyp)10/(Flp)10 and (flp)10. Interestingly, PPI helixes of (flp)10 exhibit cold denaturation in n-propanol with a value of Ts near 70°. Together, these data show that stereoelectronic effects can have a substantial impact on polyproline conformation and provide a rational means to stabilize a PPI or PPII helix.(c) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. Conformational stability of collagen relies on a stereoelectronic effect. J. Am. Chem. Soc. 2001, 123, 777– 778, DOI: 10.1021/ja005542v[ACS Full Text
], [CAS], Google Scholar192chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1Kr&md5=e098730171588bbb036f712d1b424675Conformational Stability of Collagen Relies on a Stereoelectronic EffectBretscher, Lynn E.; Jenkins, Cara L.; Taylor, Kimberly M.; DeRider, Michele L.; Raines, Ronald T.Journal of the American Chemical Society (2001), 123 (4), 777-778CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Here, we demonstrate for the first time that a stereoelectronic effect is crit. for the conformational stability of a protein. - 193Bacqué, E. Influence of fluorination at position 16 of antibacterial pristinamycins II. Chimia 2004, 58, 128– 132, DOI: 10.2533/000942904777678109
- 194Erickson, J.; McLoughlin, J. I. Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem. 1995, 60, 1626– 1631, DOI: 10.1021/jo00111a021[ACS Full Text
], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktleksrY%253D&md5=efa305f99bfa66ac92aa3b72942289b4Hydrogen Bond Donor Properties of the Difluoromethyl GroupErickson, Jon A.; McLoughlin, Jim I.Journal of Organic Chemistry (1995), 60 (6), 1626-31CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A theor. and exptl. study of the existence and the properties of the difluoromethyl group acting as a hydrogen bond donor has been carried out. An intramol. CF2H...O:C interaction was examd. using semiempirical MO calcns. of both a non-hydrogen-bonded and hydrogen-bonded conformation of a CF2H-substituted pyrazolecarboxamide fungicide. Results revealed a short H...O contact, a significant energy stabilization, and a lowering in the IR spectrum of 22 cm-1. The exptl. IR spectrum of this mol. gave two carbonyl stretching frequencies, one lower by 18 cm-1, very similar to the calcd. no. Low-temp. NMR results are also consistent with a geometry having the possibility of an intramol. CF2H...O:C hydrogen bond. The hydrogen bond in this system may be related to the enhanced biol. activity of the CF2H compd. over its CF3 counterpart. In addn., ab initio MO methods were employed to examine inter- and intramol. hydrogen-bonding models of the difluoromethyl group. The results showed that the CF2H...O:C interaction has a binding energy of ∼1.0 kcal mol-1 and a H...O distance of ∼2.4 Å. - 195(a) Walter, H.; Tobler, H.; Gribkov, D.; Corsi, D. Sedaxane, isopyrazam and solatenol: novel broad-spectrum fungicides inhibiting succinate dehydrogenase (SDH) - synthesis challenges and biological aspects. Chimia 2015, 69, 425– 434, DOI: 10.2533/chimia.2015.425 .(b) Jeschke, P. Progress of modern agricultural chemistry and future prospects. Pest Manage. Sci. 2016, 72, 433– 455, DOI: 10.1002/ps.4190[Crossref], [PubMed], [CAS], Google Scholar195bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitV2msLjF&md5=a46dd1c0017a749afdac4b8a29ebb3c7Progress of modern agricultural chemistry and future prospectsJeschke, PeterPest Management Science (2016), 72 (3), 433-455CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)Agriculture is facing an enormous challenge: it must ensure that enough high-quality food is available to meet the needs of a continually growing population. Current and future agronomic prodn. of food, feed, fuel and fiber requires innovative solns. for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands, renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chem. has to support farmers to manage these tasks. Today, the so-called 'side effects' of agrochems. regarding yield and quality are gaining more importance. Agrochem. companies with a strong research and development focus will have the opportunity to shape the future of agriculture by delivering innovative integrated solns. This review gives a comprehensive overview of the innovative products launched over the past 10 years and describes the progress of modern agricultural chem. and its future prospects. © 2015 Society of Chem. Industry.
- 196Goldberg, K.; Groombridge, S.; Hudson, J.; Leach, A. G.; MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.; Sweeney, J. Oxadiazole isomers: all bioisosteres are not created equal. MedChemComm 2012, 3, 600– 604, DOI: 10.1039/c2md20054f[Crossref], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFart7o%253D&md5=83a31c533e43296d8f681d4063f731b8Oxadiazole isomers: all bioisosteres are not created equalGoldberg, Kristin; Groombridge, Sam; Hudson, Julian; Leach, Andrew G.; MacFaul, Philip A.; Pickup, Adrian; Poultney, Ruth; Scott, James S.; Svensson, Per H.; Sweeney, JosephMedChemComm (2012), 3 (5), 600-604CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compds. were evaluated and found to have significant differences in their various phys. and pharmaceutical properties. Exptl. and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.
- 197(a) Narjes, F.; Koehler, K. F.; Koch, U.; Gerlach, B.; Colarusso, S.; Steinkuhler, C.; Brunetti, M.; Altamura, S.; De Francesco, R.; Matassa, V. G. A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease. Bioorg. Med. Chem. Lett. 2002, 12, 701– 704, DOI: 10.1016/S0960-894X(01)00842-3[Crossref], [PubMed], [CAS], Google Scholar.197ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtFKqur8%253D&md5=3797b78c5827e4db42a7170844d0c0cbA designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 proteaseNarjes, Frank; Koehler, Konrad F.; Koch, Uwe; Gerlach, Benjamin; Colarusso, Stefania; Steinkuhler, Christian; Brunetti, Mirko; Altamura, Sergio; De Francesco, Raffaele; Matassa, Victor G.Bioorganic & Medicinal Chemistry Letters (2002), 12 (4), 701-704CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The difluoromethyl group was designed by computational chem. methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor AcAspGlu-NHCH(CHPH2)CO-Glu-NHCH(CH2C6H11)CONHCH(CH2CHF2)R (I, R = CHO) Ki 30 nM and reversible covalent inhibitors (I, R = CO2H) Ki 0.5 nM; and (I, R = COCO2H) Ki* 10 pM.(b) Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.; Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V. G.; Sollazzo, M. J. Inhibition of the hepatitis C virus NS3/4A protease: the crystal structures of two protease-inhibitor complexes. J. Biol. Chem. 2000, 275, 7152– 7157, DOI: 10.1074/jbc.275.10.7152 .(c) Ontoria, J. M.; Di Marco, S.; Conte, I.; Di Francesco, M. E.; Gardelli, C.; Koch, U.; Matassa, V. G.; Poma, M.; Steinkühler, C.; Volpari, C.; Harper, S. The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease. J. Med. Chem. 2004, 47, 6443– 6446, DOI: 10.1021/jm049435d
- 198(a) Desiraju, G. R. The C-H···O hydrogen bond: structural implications and supramolecular design. Acc. Chem. Res. 1996, 29, 441– 449, DOI: 10.1021/ar950135n[ACS Full Text.
], [CAS], Google Scholar198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XltVKgsbY%253D&md5=549f714126277225e227416794716df5The C-H···O Hydrogen Bond: Structural Implications and Supramolecular DesignDesiraju, Gautam R.Accounts of Chemical Research (1996), 29 (9), 441-449CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review with 64 refs.(b) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem. 2017, 60, 797– 804, DOI: 10.1021/acs.jmedchem.6b01691[ACS Full Text.
], [CAS], Google Scholar198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis12jtw%253D%253D&md5=36159f57b99aa812693f32ff38e88406Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" ConceptZafrani, Yossi; Yeffet, Dina; Sod-Moriah, Gali; Berliner, Anat; Amir, Dafna; Marciano, Daniele; Gershonov, Eytan; Saphier, SigalJournal of Medicinal Chemistry (2017), 60 (2), 797-804CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is a growing interest in org. compds. contg. the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepd. and their drug-like properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were detd. using Abraham's solute 1H NMR anal. The difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the exptl. Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ consts. These results may aid in the rational design of drugs contg. the difluoromethyl moiety.(c) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. CF2H, a hydrogen bond donor. J. Am. Chem. Soc. 2017, 139, 9325– 9332, DOI: 10.1021/jacs.7b04457[ACS Full Text
], [CAS], Google Scholar198chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Kgtbo%253D&md5=f2345db11c3f695f3056c3c8cdad746cCF2H, a Hydrogen Bond DonorSessler, Chanan D.; Rahm, Martin; Becker, Sabine; Goldberg, Jacob M.; Wang, Fang; Lippard, Stephen J.Journal of the American Chemical Society (2017), 139 (27), 9325-9332CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The CF2H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed ty crystallog., spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CF2H groups and the important roles of CF2-H···O hydrogen bonds in influencing intermol. interactions and conformational preferences. Exptl. evidence, corroborated by theory, reveals the distinctive nature of CF2H hydrogen bonding interactions relative to their normal OH hydrogen bonding counterparts. - 199Zheng, Z. B.; D’Andrea, S. V.; Sun, L.-Q.; Wang, A. X.; Chen, Y.; Bowsher, M.; Hiebert, S.; Friborg, J.; Falk, P.; Hernandez, D.; Yu, F.; Sheaffer, A. K.; Zhai, G.; Knipe, J. O.; Mosure, K.; Rajamani, R.; Ng, A.; Gao, Q.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Sulfonamide inhibitors of hepatitis C virus NS3 protease bearing a novel P1 cyclopropyl difluoromethyl moiety. ACS Med. Chem. Lett., 2018, DOI : DOI: 10.1021/acsmedchemlett.7b00503
- 200Lin, C.-W.; Dutta, S.; Asatryan, A.; Chiu, Y.-L.; Wang, H.; Clifton, J., II; Campbell, A.; Liu, W. Pharmacokinetics, safety, and tolerability of single and multiple doses of ABT-493: a first-in-human study. J. Pharm. Sci. 2017, 106, 645– 651, DOI: 10.1016/j.xphs.2016.10.007
- 201Rodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E. GS-9857 in patients with chronic hepatitis C virus genotype 1–4 infection: a randomized, double-blind, dose-ranging phase 1 study. J. Viral Hepatitis 2016, 23, 614– 622, DOI: 10.1111/jvh.12527[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFOkurbK&md5=257769b545cb4289b8f9fc5298454f91GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 studyRodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E.Journal of Viral Hepatitis (2016), 23 (8), 614-622CODEN: JVHEER; ISSN:1365-2893. (John Wiley & Sons Ltd.)Summary : GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-assocd. variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 lab. abnormalities were obsd. in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alk. phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median max. redns. in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was assocd. with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
- 202(a) Xu, Y.; Prestwich, G. D. Concise synthesis of acyl migration-blocked 1,1-difluorinated analogues of lysophosphatidic acid. J. Org. Chem. 2002, 67, 7158– 7161, DOI: 10.1021/jo0203037[ACS Full Text.
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We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from D-mannitol 1,2:5,6-bis-acetonide to give two 1,1-difluorodeoxy analogs of (2R)-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the labile sn-2 LPA species. The 19F NMR of diastereotopic fluorines of the difluoromethyl group shows an unexpected solvent dependence.(b) Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich, G. D. Synthesis of difluoromethyl substituted lysophosphatidic acid analogues. Tetrahedron 2004, 60, 43– 49, DOI: 10.1016/j.tet.2003.11.001[Crossref], [CAS], Google Scholar202bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpslOjt7c%253D&md5=89be69d1a022068ca6daa5bd6cb9b4d1Synthesis of difluoromethyl substituted lysophosphatidic acid analoguesXu, Yong; Qian, Lian; Pontsler, Aaron V.; McIntyre, Thomas M.; Prestwich, Glenn D.Tetrahedron (2004), 60 (1), 43-49CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biol. that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogs of 2-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogs are fully active as natural LPA. - 203(a) Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Suresh, M. R.; Knaus, E. E. Synthesis of celecoxib analogues possessing an N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. J. Med. Chem. 2009, 52, 1525– 1529, DOI: 10.1021/jm8015188 .(b) Yu, G.; Praveen Rao, P. N.; Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Velázquez, C. A.; Suresh, M. R.; Knaus, E. E. Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual Inhibitors of cyclooxygenases and 5-lipoxygenase. Bioorg. Med. Chem. Lett. 2010, 20, 2168– 2173, DOI: 10.1016/j.bmcl.2010.02.040[Crossref], [PubMed], [CAS], Google Scholar203bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjslGmtrg%253D&md5=10042762346b7c2e0e9794d9c470f163Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual inhibitors of cyclooxygenases and 5-lipoxygenaseYu, Gang; Praveen Rao, P. N.; Chowdhury, Morshed A.; Abdellatif, Khaled R. A.; Dong, Ying; Das, Dipankar; Velazquez, Carlos A.; Suresh, Mavanur R.; Knaus, Edward E.Bioorganic & Medicinal Chemistry Letters (2010), 20 (7), 2168-2173CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A new group of acetic acid and propionic acid regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compds. exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isoenzyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, i.e., absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid (I) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Mol. modeling (docking) studies showed that the highly electroneg. CHF2 substituent present in I, that showed a modest selectivity for the COX-2 isoenzyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO2NH2) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region contg. the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.
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], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvF2nsLY%253D&md5=69f0655b7ff06aee79054c470aefe66cFluorinated Phosphonates: Synthesis and Biomedical ApplicationRomanenko, Vadim D.; Kukhar, Valery P.Chemical Reviews (Washington, DC, United States) (2006), 106 (9), 3868-3935CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The synthesis, fundamental chem. properties, and biomedical uses of the phosphonic acid derivs. that bear at least one F substituent on the organyl moiety are the subject of this review, which is organized as follows. The 1st part is a survey of synthetic methods used for the prepn. of fluorinated phosphonates. The 2nd part consists of a presentation of the different types of fluorophosphonates having significant biol. importance. The 3rd part describes the use of fluorinated phosphonates in biomedical studies (e.g. enzyme inhibitors, catalytic antibodies, antiviral agents, antitumor agents, anti-platelet-aggregation agents). Discussion of basic aspects of phosphonate and organofluorine chem. is reduced to min. to avoid redundancy to the long series of papers already published in journals and books. Also no particular attention will be paid to subjects that have recently been reviewed. In such cases, only the most important trends are briefly summarized. Literature coverage for the review extends up to Apr. 2006. - 205(a) Blackburn, G. M.; Kent, D. E. A novel synthesis of R- and γ-fluoroalkylphosphonates. J. Chem. Soc., Chem. Commun. 1981, 511– 513, DOI: 10.1039/C39810000511 .(b) Blackburn, G. M.; England, D. A.; Kolkmann, F. Monofluoro and difluoro-methylenebisphosphonic acids: isopolar analogues of pyrophosphoric acid. J. Chem. Soc., Chem. Commun. 1981, 930– 932, DOI: 10.1039/c39810000930
- 206(a) Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jaina, S. C. The difluoromethylenephosphonate moiety as a phosphate mimic: X-ray structure of 2-amino-1,1,-difluoroethylphosphonic acid. J. Chem. Soc., Chem. Commun. 1990, 1053– 1054, DOI: 10.1039/c39900001053 .(b) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard, J. A. K. Synthesis of monofluoro- and difluoro- methylenephopshonate analogues of sn-glycerol-3-phosphate as substrates for glycerol-3-phosphate dehydrogenase and the X-ray structure of the fluoromethylenephosphonate moiety. Tetrahedron 1996, 52, 165– 176, DOI: 10.1016/0040-4020(95)00890-K .(c) O’Hagan, D.; Rzepa, H. S. Some influences of fluorine in bioorganic chemistry. Chem. Commun. 1997, 645– 652, DOI: 10.1039/a604140j[Crossref], [CAS], Google Scholar.206chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXislGlu7g%253D&md5=6d37429e3baff14d46d1d24355eb2d86Some influences of fluorine in bioorganic chemistryO'Hagan, David; Rzepa, Henry S.Chemical Communications (Cambridge) (1997), (7), 645-652CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review with 76 refs. The stereochem. outcome on processing fluorinated substrate analogs by enzymes can often be controlled by electronic and stereoelectronic factors assocd. with the fluorine atoms. Interpreting or predicting the behavior of fluorinated compds. is complex and has led to the term flustrates (fluorine-contg. substrates) being coined. However, a greater appreciation of the electronic and stereoelectronic properties of org. fluorine renders the behavior of these compds. more interpretable.(d) Thatcher, G. R. J.; Campbell, A. S. Phosphonates as mimics of phosphate biomolecules: Ab initio calculations on tetrahedral ground states and pentacoordinate intermediates for phosphoryl transfer. J. Org. Chem. 1993, 58, 2272– 2281, DOI: 10.1021/jo00060a050
- 207Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. New prospects toward the synthesis of difluoromethylated phosphate mimics. Chem. - Eur. J. 2016, 22, 10284– 10293, DOI: 10.1002/chem.201601310[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGjurnM&md5=8ff2358df5c30d58ce2f1f970a6623a8New Prospects toward the Synthesis of Difluomethylated Phosphate MimicsIvanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, ThomasChemistry - A European Journal (2016), 22 (30), 10284-10293CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review of the prepn., reactions and biolical activities of difluoromethylated phosphonate-contg. mols. The difluoromethyl phosphonate motif plays a crucial role in the development of bioactive mols. as it is considered as a phosphate bioisoster. Since 2010, a renewal of interest to enlarge the panel of reactions to access these difluoromethylated phosphonate-contg. mols. was witnessed. This Concept article charts the recent progress that was made.
- 208(a) Bialy, L.; Waldmann, H. Inhibitors of protein tyrosine phosphatases: next-generation drugs?. Angew. Chem., Int. Ed. 2005, 44, 3814– 3839, DOI: 10.1002/anie.200461517[Crossref], [CAS], Google Scholar.208ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFGisr8%253D&md5=a8bcd03851b638cc6d3e6ab2466eb97bInhibitors of protein tyrosine phosphatases: Next-generation drugs?Bialy, Laurent; Waldmann, HerbertAngewandte Chemie, International Edition (2005), 44 (25), 3814-3839CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The protein tyrosine phosphatases (PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurol. disorders and diabetes. Consequently, PTPs have emerged as promising targets for therapeutic intervention in recent years. In this review, general aspects of PTPs and the development of small-mol. inhibitors of PTPs by both academic research groups and pharmaceutical companies are discussed. Different strategies have been successfully applied to identify potent and selective inhibitors. These studies constitute the basis for the future development of PTP inhibitors as drugs.(b) Combs, A. P. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J. Med. Chem. 2010, 53, 2333– 2344, DOI: 10.1021/jm901090b[ACS Full Text
], [CAS], Google Scholar208bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFektLzJ&md5=700b2a519c670e1bd9cb41af271d62aeRecent Advances in the Discovery of Competitive Protein Tyrosine Phosphatase 1B Inhibitors for the Treatment of Diabetes, Obesity, and CancerCombs, Andrew P.Journal of Medicinal Chemistry (2010), 53 (6), 2333-2344CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. - 209(a) Smyth, M. S.; Ford, H., Jr.; Burke, T. R., Jr. A general method for the preparation of benzylic R,R-difluorophosphonic acids; nonhydrolyzable mimetics of phosphotyrosine. Tetrahedron Lett. 1992, 33, 4137– 4140, DOI: 10.1016/S0040-4039(00)74672-7 .(b) Ivanova, M. V.; Bayle, A.; Besset, T.; Poisson, T.; Pannecoucke, X. Copper-mediated formation of aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates: a general approach to fluorinated phosphate mimics. Angew. Chem., Int. Ed. 2015, 54, 13406– 13410, DOI: 10.1002/anie.201507130[Crossref], [CAS], Google Scholar.209bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2nsrbP&md5=3d705f0582fc16afbb0df60329c9e715Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate MimicsIvanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Poisson, Thomas; Pannecoucke, XavierAngewandte Chemie, International Edition (2015), 54 (45), 13406-13410CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodol. using TMSCF2PO(OEt)2, iodonium salts and a Cu salt provided a straightforward manifold to reach these highly relevant products. The reaction proved to be highly functional group tolerant and proceeded under mild conditions, giving the corresponding products in good to excellent yields. This method represents the 1st general synthetic route to this important class of fluorinated scaffolds, which are well-recognized as in vivo stable phosphate surrogates.(c) Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. Copper-mediated introduction of the CF2PO(OEt)2 motif: scope and limitations. Chem. - Eur. J. 2017, 23, 17318– 17338, DOI: 10.1002/chem.201703542[Crossref], [PubMed], [CAS], Google Scholar209chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWntbzP&md5=d46a0ae6241cd7b5e38ddb34f20cfdd5Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope and LimitationsIvanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, ThomasChemistry - A European Journal (2017), 23 (68), 17318-17338CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Herein, a general procedure to access CF2PO(OEt)2-contg. mols. is reported. The reagent CuCF2PO(OEt)2 is accessible by a simple protocol and a broad range of substrates can be functionalized. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated mols. at room temp. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalized, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF2PO(OEt)2-contg. mols.
- 210(a) Panigrahi, K.; Eggen, M.; Maeng, J.-H.; Shen, Q.; Berkowitz, D. B. The α,α-difluorinated phosphonate L-pSer-analogue: an accessible chemical tool for studying kinase-dependent signal transduction. Chem. Biol. 2009, 16, 928– 936, DOI: 10.1016/j.chembiol.2009.08.008[Crossref], [PubMed], [CAS], Google Scholar.210ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFynsL3I&md5=a0ece823d48b1197f6a4f16a52f9a3a9The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal TransductionPanigrahi, Kaushik; Eggen, MariJean; Maeng, Jun-Ho; Shen, Quanrong; Berkowitz, David B.Chemistry & Biology (Cambridge, MA, United States) (2009), 16 (9), 928-936CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)A review. This overview focuses on the (α,α-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chem. biol. tools are discussed, organized by method of PCF2-C bond formation. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chem. biol. approach include the regulation of p53 tumor suppressor protein activity and of melatonin prodn. Given these successes, the future is bright for the use of such "teflon phospho-amino acid mimics" to map kinase-based signaling pathways.(b) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a phosphoserine mimetic prodrug with potent 14–3-3 protein inhibitory activity. Chem. Biol. 2012, 19, 764– 771, DOI: 10.1016/j.chembiol.2012.05.011[Crossref], [PubMed], [CAS], Google Scholar210bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptVKlsLo%253D&md5=712ae5cf745751cf2ccbc3c585ff96caSynthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory ActivityArrendale, Allison; Kim, Keunho; Choi, Jun Young; Li, Wei; Geahlen, Robert L.; Borch, Richard F.Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (6), 764-771CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs contg. phosphorylated serine and threonine residues. To create small mols. that inhibit such interactions, we developed methodol. for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small mol. inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concns. when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concn.-dependent manner that correlates well with its ability to inhibit cell growth. This methodol. can be applied to target a variety of proteins contg. phosphoserine and other phosphoamino acid binding domains.
- 211(a) Rye, C. S.; Baell, J. B. Phosphate isosteres in medicinal chemistry. Curr. Med. Chem. 2005, 12, 3127– 3141, DOI: 10.2174/092986705774933452[Crossref], [PubMed], [CAS], Google Scholar.211ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlSqsrbJ&md5=585a42ff8051b687939a70055612fab5Phosphate isosteres in medicinal chemistryRye, C. S.; Baell, J. B.Current Medicinal Chemistry (2005), 12 (26), 3127-3141CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. The phosphate group is at the heart of an enormous no. of biol. processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biol. activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognize the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chem. research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognizing domains such as Src homol. 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilization of the phosphate moiety as part of an inhibitor is severely limited by the enzymic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favorably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylene phosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the mol. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chem., covering roughly the past four years.(b) Elliott, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. The use of phosphate bioisosteres in medicinal chemistry and chemical biology. MedChemComm 2012, 3, 735– 751, DOI: 10.1039/c2md20079a[Crossref], [CAS], Google Scholar.211bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsVShsr0%253D&md5=6a6a7b53bd71aaa052df27cefae38036The use of phosphate bioisosteres in medicinal chemistry and chemical biologyElliott, Thomas S.; Slowey, Aine; Ye, Yulin; Conway, Stuart J.MedChemComm (2012), 3 (7), 735-751CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. Phosphate and pyrophosphate groups play a central role in cellular signalling and consequently are of great interest to both medicinal chemists and chem. biologists. However, the design of mols. that can interfere with phosphate-based processes is recognized as a significant challenge, esp. when the resulting compds. must show good cellular penetration and stability. Herein, we have reviewed the full range of phosphate bioisosteres currently reported and provided the context of their deployment. We aim to provide a useful ref. for medicinal chemists and chem. biologists who are engaged in the design of mols. that target phosphate-binding proteins.(c) Zhang, Y.; Borrel, A.; Ghemtio, L.; Regad, L.; Boije af Gennäs, G.; Camproux, A.-C.; Yli-Kauhaluoma, J.; Xhaard, H. Structural isosteres of phosphate groups in the protein data bank. J. Chem. Inf. Model. 2017, 57, 499– 516, DOI: 10.1021/acs.jcim.6b00519[ACS Full Text
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- 215Hakogi, T.; Yamamoto, T.; Fujii, S.; Ikeda, K.; Katsumura, S. Synthesis of sphingomyelin difluoromethylene analogue. Tetrahedron Lett. 2006, 47, 2627– 2630, DOI: 10.1016/j.tetlet.2006.02.018[Crossref], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xitlarsbo%253D&md5=a50d891bb2c469fbfb8e2fadf044ee0aSynthesis of sphingomyelin difluoromethylene analogHakogi, Toshikazu; Yamamoto, Tetsuya; Fujii, Shinobu; Ikeda, Kiyoshi; Katsumura, ShigeoTetrahedron Letters (2006), 47 (15), 2627-2630CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)As a new sphingomyelinase inhibitor, a novel sphingomyelin CF2 analog was designed and synthesized. One key step of this synthesis is the very mild hydrolysis of the oxazolidinone ring of methylphosphonate I, a suitable intermediate for the introduction of a di-Et difluoro-methylphosphonate group, by utilizing the characteristic electron withdrawing nature of the group at the oxazolidinone ring in an alc. solvent to produce the corresponding carbonate attaching at the secondary hydroxy group. The synthesized CF2 analog inactivated toward B. cereus sphingomyelinase with nearly the same attitude as the nitrogen analog that we previously reported.
- 216(a) Lapierre, J.; Ahmed, V.; Chen, M.-J.; Ispahany, M.; Guillemette, J. G.; Taylor, S. D. The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 151– 155, DOI: 10.1016/j.bmcl.2003.09.089[Crossref], [PubMed], [CAS], Google Scholar.216ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvVWntLY%253D&md5=951b12f71bdbd87fd99a02ce879f955dThe difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitorsLapierre, Jennifer; Ahmed, Vanessa; Chen, Mei-Jin; Ispahany, Mehdi; Guillemette, J. Guy; Taylor, Scott D.Bioorganic & Medicinal Chemistry Letters (2004), 14 (1), 151-155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)Several estrone sulfate and estradiol sulfate analogs, in which the sulfate group was replaced with an α,α-difluoromethylenesulfonate group or an α,α-difluoromethylenetetrazole group, were examd. as inhibitors of steroid sulfatase (STS). These compds. were 4.5-10.5 times more potent than their non-fluorinated analogs. Moreover, the presence of the fluorines changed the mode of inhibition from mixed to competitive. The inhibitor bearing the α,α-difluoromethylenetetrazole group exhibited an affinity for STS approaching that of the natural STS substrate, estrone sulfate. Possible reasons for the enhanced affinity of the fluorinated compds. compared to their non-fluorinated counterparts are discussed.(b) Liu, Y.; Ahmed, V.; Hill, B.; Taylor, S. D. Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor. Org. Biomol. Chem. 2005, 3, 3329– 3335, DOI: 10.1039/b508852f[Crossref], [PubMed], [CAS], Google Scholar216bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpsFWnsbo%253D&md5=3cf8ae7e607a93f7d35b8677bcf76625Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitorLiu, Yong; Ahmed, Vanessa; Hill, Bryan; Taylor, Scott D.Organic & Biomolecular Chemistry (2005), 3 (18), 3329-3335CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analog bearing an α,α-difluorosulfonamide moiety at the 3-position on the A-ring, I, was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pKa of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was detd. to be 8.05 using 19F NMR. I is a reversible inhibitor with a Ki similar to that of its sulfonate analog at pH 7.0. It is more potent than its nonfluorinated sulfonamide analog and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.
- 217(a) Maltais, R.; Poirier, D. Steroid sulfatase inhibitors: a review covering the promising 2000–2010 decade. Steroids 2011, 76, 929– 948, DOI: 10.1016/j.steroids.2011.03.010 .(b) Mostafa, Y. A.; Taylor, S. D. Steroid derivatives as inhibitors of steroid sulfatase. J. Steroid Biochem. Mol. Biol. 2013, 137, 183– 198, DOI: 10.1016/j.jsbmb.2013.01.013[Crossref], [PubMed], [CAS], Google Scholar217bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXislyltbk%253D&md5=920cbdc85ea6cd9680f01b62330f9a1bSteroid derivatives as inhibitors of steroid sulfataseMostafa, Yaser A.; Taylor, Scott D.Journal of Steroid Biochemistry and Molecular Biology (2013), 137 (), 183-198CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)A review. Sulfated steroids function as a storage reservoir of biol. active steroid hormones. The sulfated steroids themselves are biol. inactive and only become active in vivo when they are converted into their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS are considered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast, prostate and endometrial cancer. The present review summarizes steroid derivs. as inhibitors of STS covering the literature from the early years of STS inhibitor development to Oct. of 2012. A brief discussion of the function, structure and mechanism of STS and its role in estrogen receptor-pos. (ER+) hormone-dependent breast cancer is also presented.This article is part of a Special Issue entitled "Synthesis and biol. testing of steroid derivs. as inhibitors".
- 218Kotoris, C. K.; Chen, M.-J.; Taylor, S. D. Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. Lett. 1998, 8, 3275– 3280, DOI: 10.1016/S0960-894X(98)00598-8
- 219Lomelino, C.; McKenna, R. Carbonic anhydrase inhibitors: a review on the progress of patent literature (2011–2016). Expert Opin. Ther. Pat. 2016, 26, 947– 956, DOI: 10.1080/13543776.2016.1203904[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFCrtb3K&md5=76c935b7b64cbe4d9c8e7710ee68bc1dCarbonic anhydrase inhibitors: a review on the progress of patent literature (2011-2016)Lomelino, Carrie; McKenna, RobertExpert Opinion on Therapeutic Patents (2016), 26 (8), 947-956CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)Introduction: A large area of carbonic anhydrase (CA) research focuses on the inhibition of human CA IX and CA XII, as these isoforms have been designated as biomarkers and therapeutic targets for various cancer types. Areas covered: Recently, the majority of CA inhibitor (CAI) patents cover compd. design, synthesis, and delivery methods for the treatment of glaucoma and cancer. The anal. of included patents highlights the need for isoform specific inhibitors. This review covers the patents of medically relevant carbonic anhydrase inhibitors between 2011-2016. Expert opinion: The improvement of structure-based drug design methods and access to the crystal structures of human CA isoforms have improved inhibitor development. This progress can be obsd. in relation to the selective inhibition of CA IX for cancer treatments, with one inhibitor in clin. trials. However, the design of nonclassical CAIs is essential to further improve isoform specificity and prevent sulfur allergies.
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- 222Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFemsbY%253D&md5=478b70744312c01d3a43cf435d9598dePredicting and tuning physicochemical properties in lead optimization: amine basicitiesMorgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, KlausChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
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- 225Huang, H.; Hutta, D. A.; Rinker, J. M.; Hu, H.; Parsons, W. H.; Schubert, C.; DesJarlais, R. L.; Crysler, C. S.; Chaikin, M. A.; Donatelli, R. R.; Chen, Y.; Cheng, D.; Zhou, Z.; Yurkow, E.; Manthey, C. L.; Player, M. R. Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J. Med. Chem. 2009, 52, 1081– 1099, DOI: 10.1021/jm801406h
- 226Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam, C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.; Slingsby, B. P.; Swarbrick, M. E. Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain. Bioorg. Med. Chem. Lett. 2010, 20, 465– 468, DOI: 10.1016/j.bmcl.2009.11.117[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsF2itb%252FN&md5=9848ef9b152eee020cfb77960e820728Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory painGleave, Robert J.; Beswick, Paul J.; Brown, Andrew J.; Giblin, Gerard M. P.; Goldsmith, Paul; Haslam, Carl P.; Mitchell, William L.; Nicholson, Neville H.; Page, Lee W.; Patel, Sadhana; Roomans, Susan; Slingsby, Brian P.; Swarbrick, Martin E.Bioorganic & Medicinal Chemistry Letters (2010), 20 (2), 465-468CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of 3-amino-6-aryl-pyridazines have been identified as CB2 agonists with high efficacy and selectivity against the CB1 receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analog I, a compd. with high potency in an in vivo model of inflammatory pain.
- 227(a) Sundar, B. G.; Bailey, T. R.; Dunn, D.; Hostetler, G. A.; Chatterjee, S.; Bacon, E. R.; Yue, C.; Schweizer, D.; Aimone, L. D.; Gruner, J. A.; Lyons, J.; Raddatz, R.; Lesur, B. Novel morpholine ketone analogs as potent histamine H3 receptor inverse agonists with wake activity. Bioorg. Med. Chem. Lett. 2012, 22, 1546– 1549, DOI: 10.1016/j.bmcl.2012.01.004 .(b) Zulli, A.; Aimone, L. D.; Mathiasen, J. R.; Gruner, J. A.; Raddatz, R.; Bacon, E. R.; Hudkins, R. L. Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists. Bioorg. Med. Chem. Lett. 2012, 22, 2807– 2810, DOI: 10.1016/j.bmcl.2012.02.081
- 228Garton, N. S.; Barker, M. D.; Davis, R. P.; Douault, C.; Hooper-Greenhill, E.; Jones, E.; Lewis, H. D.; Liddle, J.; Lugo, D.; McCleary, S.; Preston, A. G. S.; Ramirez-Molina, C.; Neu, M.; Shipley, T. J.; Somers, D. O.; Watson, R. J.; Wilson, D. M. Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 4606– 4612, DOI: 10.1016/j.bmcl.2016.08.070
- 229Ahmad, S.; Washburn, W. N.; Hernandez, A. S.; Bisaha, S.; Ngu, K.; Wang, W.; Pelleymounter, M. A.; Longhi, D.; Flynn, N.; Azzara, A. V.; Rohrbach, K.; Devenny, J.; Rooney, S.; Thomas, M.; Glick, S.; Godonis, H.; Harvey, S.; Zhang, H.; Gemzik, B.; Janovitz, E. B.; Huang, C.; Zhang, L.; Robl, J. A.; Murphy, B. J. Synthesis and antiobesity properties of 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): a highly efficacious melanin concentrating hormone receptor 1 (MCHR1) inhibitor. J. Med. Chem. 2016, 59, 8848– 8858, DOI: 10.1021/acs.jmedchem.6b00676
- 230(a) Deliencourt-Godefroy, G.; Lopes, L. Family of Aryl, Heteroaryl, O-Aryl and O-Heteroaryl Carbasugars. World Patent Application WO 2012/160218, Nov. 29, 2012.(b) Chen, Z.-H.; Wang, R.-W.; Qing, F.-L. Synthesis and biological evaluation of SGLT2 inhibitors: gem-difluoromethylenated dapagliflozin analogs. Tetrahedron Lett. 2012, 53, 2171– 2176, DOI: 10.1016/j.tetlet.2012.02.062
- 231(a) Berry, C. B.; Bubser, M.; Jones, C. K.; Hayes, J. P.; Wepy, J. A.; Locuson, C. W.; Daniels, J. S.; Lindsley, C. W.; Hopkins, C. R. Discovery and characterization of ML398, a potent and selective antagonist of the D4 receptor with in vivo activity. ACS Med. Chem. Lett. 2014, 5, 1060– 1064, DOI: 10.1021/ml500267c .(b) Witt, J. O.; McCollum, A. L.; Hurtado, M. A.; Huseman, E. D.; Jeffries, D. E.; Temple, K. J.; Plumley, H. C.; Blobaum, A. L.; Lindsley, C. W.; Hopkins, C. R. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists. Bioorg. Med. Chem. Lett. 2016, 26, 2481– 2488, DOI: 10.1016/j.bmcl.2016.03.102
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- 233Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Direct synthesis of fluorinated heteroarylether bioisosteres. Angew. Chem., Int. Ed. 2013, 52, 3949– 3952, DOI: 10.1002/anie.201300763[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsVOhu7k%253D&md5=14e8d7c1d2f0494de4b5f78a11f5aa6cDirect Synthesis of Fluorinated Heteroarylether BioisosteresZhou, Qianghui; Ruffoni, Alessandro; Gianatassio, Ryan; Fujiwara, Yuta; Sella, Eran; Shabat, Doron; Baran, Phil S.Angewandte Chemie, International Edition (2013), 52 (14), 3949-3952CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A modular synthesis of reagents (e.g. sodium 1,1-difluoroethylsulfinate) that can be used for direct incorporation of 1,1-difluoroalkyl groups onto various heterocycles is reported. The scope and generality of the incorporation of difluoroalkyl groups is exemplified with the 1,1-difluoroethyl group, and a proof of principle is shown for a general synthesis of fluorinated heteroaryl ether bioisosteres.
- 234Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Potent, Highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. J. Am. Chem. Soc. 2010, 132, 14229– 14238, DOI: 10.1021/ja106175q[ACS Full Text
], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmt7nP&md5=7d9f72450e01f2dd53e4c07eb4e88eedPotent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide SynthaseXue, Fengtian; Li, Huiying; Delker, Silvia L.; Fang, Jianguo; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.Journal of the American Chemical Society (2010), 132 (40), 14229-14238CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compds., e.g., I, contg. a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compds., (S,S) vs. (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compds. with monocationic character under physiol. pH conditions. Biol. evaluations have led to a nNOS inhibitor with a Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calcns. indicated that the low pKa NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compd. to the parent mol. shows 22% for the difluorinated compd. vs. essentially no oral bioavailability for the parent compd. This indicates that the goal of this research to make compds. with only one protonated nitrogen atom at physiol. pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished. - 235Anderson, M. O.; Zhang, J.; Liu, Y.; Yao, C.; Phuan, P.-W.; Verkman, A. S. Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J. Med. Chem. 2012, 55, 5942– 5950, DOI: 10.1021/jm300491y[ACS Full Text
], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1Snur4%253D&md5=a1140ee5f316022648a8140fbd6607dfNanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-BAnderson, Marc O.; Zhang, Jicheng; Liu, Yan; Yao, Chenjuan; Phuan, Puay-Wah; Verkman, A. S.Journal of Medicinal Chemistry (2012), 55 (12), 5942-5950CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic ('urearetic') mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC50 = 25.1 nM and reduced urinary concn. in mice (Yao et al. J. Am. Soc. Nephrol., in press). Here, we analyzed com. available analogs of (I) to establish a structure-activity series and synthesized a targeted library of 11 analogs to identify potent, metabolically stable UT-B inhibitors. The best compd., {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, (II), had IC50 of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, resp., and ∼40-fold improved in vitro metabolic stability compared to I. In mice, II accumulated in kidney and urine and reduced max. urinary concn. Triazolothienopyrimidine may be useful for therapy of diuretic-refractory edema in heart and liver failure. - 236Piotrowski, D. W.; Futatsugi, K.; Warmus, J. S.; Orr, S. T.M.; Freeman-Cook, K. D.; Londregan, A. T.; Wei, L.; Jennings, S. M.; Herr, M.; Coffey, S. B.; Jiao, W.; Storer, G.; Hepworth, D.; Wang, J.; Lavergne, S. Y.; Chin, J. E.; Hadcock, J. R.; Brenner, M. B.; Wolford, A. C.; Janssen, A. M.; Roush, N. S.; Buxton, J.; Hinchey, T.; Kalgutkar, A. S.; Sharma, R.; Flynn, D. A. Identification of tetrahydropyrido[4,3-d]pyrimidine amides as a new class of orally bioavailable TGR5 agonists. ACS Med. Chem. Lett. 2013, 4, 63– 68, DOI: 10.1021/ml300277t[ACS Full Text
], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1GlsrfP&md5=7806a5272db5d3b6bc935f6df38a2b04Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 AgonistsPiotrowski, David W.; Futatsugi, Kentaro; Warmus, Joseph S.; Orr, Suvi T. M.; Freeman-Cook, Kevin D.; Londregan, Allyn T.; Wei, Liuqing; Jennings, Sandra M.; Herr, Michael; Coffey, Steven B.; Jiao, Wenhua; Storer, Gregory; Hepworth, David; Wang, Jian; Lavergne, Sophie Y.; Chin, Janice E.; Hadcock, John R.; Brenner, Martin B.; Wolford, Angela C.; Janssen, Ann M.; Roush, Nicole S.; Buxton, Joanne; Hinchey, Terri; Kalgutkar, Amit S.; Sharma, Raman; Flynn, Declan A.ACS Medicinal Chemistry Letters (2013), 4 (1), 63-68CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biol. target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of I, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that I could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5. - 237(a) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in drug design: a case study with fluoroanisoles. ChemMedChem 2015, 10, 715– 726, DOI: 10.1002/cmdc.201402555[Crossref], [PubMed], [CAS], Google Scholar.237ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvVWku7Y%253D&md5=45dbead703594c31581cc6c7e62d1b81Fluorine in Drug Design: A Case Study with FluoroanisolesXing, Li; Blakemore, David C.; Narayanan, Arjun; Unwalla, Ray; Lovering, Frank; Denny, R. Aldrin; Zhou, Huanyu; Bunnage, Mark E.ChemMedChem (2015), 10 (4), 715-726CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addn. to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochem. and pharmacokinetic properties. Anal. of anisole and fluoroanisole matched mol. pairs in the Pfizer corporate database reveals interesting trends: (1) PhOCF3 increases log D by ∼1 log unit over PhOCH3 compds.; (2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and (3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3. Emerging from the investigation, difluoroanisole (PhOCF2H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, the anal. suggests PhOCF2H may be a more attractive alternative, and greater exploitation of this motif is recommended.(b) Jeschke, P.; Baston, E.; Leroux, F. R. α-Fluorinated ethers as “exotic” entity in medicinal chemistry. Mini-Rev. Med. Chem. 2007, 7, 1027– 1034, DOI: 10.2174/138955707782110150[Crossref], [PubMed], [CAS], Google Scholar237bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1Sjs7fN&md5=ad28d99858f35257c9bec151e6a4db9aα-Fluorinated ethers as "exotic" entity in medicinal chemistryJeschke, Peter; Baston, Eckhard; Leroux, Frederic R.Mini-Reviews in Medicinal Chemistry (2007), 7 (10), 1027-1034CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacol. drugs, neurol. drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chem.
- 238(a) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis. J. Chem. Inf. Model. 2008, 48, 1– 24, DOI: 10.1021/ci7002494[ACS Full Text.
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Abstract

Figure 1

Figure 1. Key drug–target interactions between 29 and the PI3Kα enzyme and conformational bias provided by an intramolecular O to S interaction.
Figure 2

Figure 2. Atropoisomerism associated with 4-(perfluoropropan-2-yl)-1H-indazol-5-amine.
Scheme 1
Scheme 1. Metabolism of 63 and the Release of 66Scheme 2
Scheme 2. Metabolic Activation Pathway Deduced for the DPP-4 Inhibitor 67Scheme 3
Scheme 3. Cytochrome P450-Mediated Metabolism of the 1,3-Benzodioxole Moiety to a MI ComplexFigure 3

Figure 3. Preferred conformation of 82 at the GABAA receptor (A) and the GABAC receptor and the transaminase enzyme (B) deduced from an evaluation of 83 and 84.
Figure 4

Figure 4. Proposed active conformation of NMDA at the GluN2A and GluN2B receptors after analysis of 91 and 92.
Figure 5

Figure 5. Conformational preferences of N-acetyl-proline methyl ester (94) (A), N-acetyl-4-(R)-fluoro-l-proline methyl ester (95) (B), and N-acetyl-4-(S)-fluoro-l-proline methyl ester (96) (C).
Figure 6

Figure 6. Acetamide conformation of 94 depicting an n → π* interaction.
Figure 7

Figure 7. Geometry of 1,1-difluoroalkanes (A), the 1,4-di-CF2 motif (B), and conformational preferences for 1,2-difluoro- (C) and 1,3-difluoro-alkanes (D).
Scheme 4
Scheme 4. Metabolism of 132Figure 8

Figure 8. Core structures of MMPs of N-phenylamides and benzamides examined in a PAMPA.
Figure 9

Figure 9. Comparison of the dipole moments and vectors of difluorinated benzenes and azines.
Figure 10

Figure 10. Key interactions between CHK1 kinase and 190 in the cocrystal structure.
Figure 11

Figure 11. Structures and cathepsin L inhibitory data for 195–204.
Figure 12

Figure 12. Proposed relationship between a piperazine lone pair of electrons and the fluorine atom of a 4-fluoropiperidine ring.
Figure 13

Figure 13. Key interactions between inhibitor 218 and thrombin.
Figure 14

Figure 14. Key drug–target interactions between the CF3 substituent of 224 and the p53 protein.
Figure 15

Figure 15. Key drug–target interactions between inhibitor 227 and BTK.
Figure 16

Figure 16. Calculated energies of the σ-hole and π-hole associated with perfluorotoluene.
Figure 17

Figure 17. Key interactions between 234 and IDH2 in the cocrystal stucture.(110b)
Figure 18

Figure 18. Key interactions between 235 and the NmrA-like family domain containing protein 1 NMRAL1 in the cocrystal complex.(111)
Figure 19

Figure 19. Proposed dipole interactions between 248 and Aurora A kinase leading to a conformational change in the DFG loop of the enzyme.
Figure 20

Figure 20. Dipole moments and vectors that illustrate isosterism between an amide moiety and fluorinated alkene derivatives that contrasts with simpler alkenes.
Figure 21

Figure 21. Key interactions between and FVIIa and the benzamidine-based inhibitor 304.
Figure 22

Figure 22. Key drug–target interactions between 309 and the HCV NS5B polymerase protein.
Figure 23

Figure 23. Key drug–target interactions between MEK1 and inhibitor 314.
Figure 24

Figure 24. Structural overlays of 82 with 318 and 319 illustrating C–F and C═O mimicry.
Scheme 5
Scheme 5. Metabolism of 331–333 by Steroid 5α-ReductaseScheme 6
Scheme 6. Reaction Process Catalyzed by α,β-Dihydroxyacid DehydrataseFigure 25

Figure 25. Isosteric relationship between formaldehyde and 1,1-difluoroethylene.
Scheme 7
Scheme 7. TDP-l-rhamnose Synthase-Catalyzed Reduction of 342 to 343Scheme 8
Scheme 8. Postulated Reaction Pathway of 341 with TDP-l-rhamnose SynthaseFigure 26

Figure 26. Incorporation of the CF3CH2NH motif in a polypeptide backbone in register (B) or in a partially retro-inverted configuration (C) that mimics the amide of a conventional polypeptide (A).
Figure 27

Figure 27. Functional aspects of the mimicry between an amide and a sulfonamide moiety and CF3CH2NH and CHF2CH2NH.
Figure 28

Figure 28. Bond angles and lengths that illustrate topological mimesis between a urea and a fluoroenamide.
Figure 29

Figure 29. Calculated conformational preferences for α-fluoromethyl and α,α-difluoromethyl secondary amides.
Figure 30

Figure 30. Conformational preferences of the α-fluorinated enantiomers of 413 designed to illuminate the bound conformation.
Figure 31

Figure 31. Topologies and bond lengths associated with α-fluoro-substituted amides 416–418 and urea 419 in the solid state.
Figure 32

Figure 32. Preferred conformation of a 2′-α-fluoro-substituted ribose compared with a 2′-β-fluoro substituted isomer and a 2′-β, 2′-α-difluoro-substituted ribose ring.
Figure 33

Figure 33. Key H-bonding interactions between a 2′-methyl ribose moiety (436) and the 2′-fluoro-2′-methyl homologue that is the ribose hallmark of 434.
Figure 34

Figure 34. Intermolecular H-bond observed in the single-crystal X-ray structure of oxadiazole 449.
Figure 35

Figure 35. Illustration of the functional mimicry between RSH and RCF2H in P1 residues incorporated into 450 and 452.
Figure 36

Figure 36. Geometric parameters for the phosphate, phosphonate, and difluoromethylenephosphonate moieties.
Figure 37

Figure 37. Proposed isosterism between anisole and (1,1-difluoroethyl)benzene.
Figure 38

Figure 38. Conformational aspects of anisole, PhOCF3, and PhOCHF2.
Figure 39

Figure 39. Comparison of the shapes of the CF3 and SF5 substituents.
Figure 40

Figure 40. Proposed drug–target interactions between 554 and T. cruzi trypanothione reductase based on docking of the ligand into the active site of the enzyme.
References
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ChemBioChem 2004, 5, 637– 643, DOI: 10.1002/cbic.200301023[Crossref], [PubMed], [CAS], Google Scholar.4fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3it1egug%253D%253D&md5=fa5ca2cfc278b83c80d5c96b18dfe312Fluorine in medicinal chemistryBohm Hans-Joachim; Banner David; Bendels Stefanie; Kansy Manfred; Kuhn Bernd; Muller Klaus; Obst-Sander Ulrike; Stahl MartinChembiochem : a European journal of chemical biology (2004), 5 (5), 637-43 ISSN:1439-4227.Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.(g) Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881– 1886, DOI: 10.1126/science.1131943[Crossref], [PubMed], [CAS], Google Scholar.4ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVOlt7rN&md5=f804876c801518e48d0bdb7d87b7fb1cFluorine in Pharmaceuticals: Looking Beyond IntuitionMueller, Klaus; Faeh, Christoph; Diederich, FrancoisScience (Washington, DC, United States) (2007), 317 (5846), 1881-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all phys. and adsorption, distribution, metab., and excretion properties of a lead compd. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on mol. conformation of the drug, has only recently begun. Here, we review exptl. progress in this vein and add complementary anal. based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.(h) Shah, P.; Westwell, A. D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem. 2007, 22, 527– 540, DOI: 10.1080/14756360701425014[Crossref], [PubMed], [CAS], Google Scholar.4hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFOjtr%252FI&md5=58bc1c42a7525b66772967543256a7d2The role of fluorine in medicinal chemistryShah, Poonam; Westwell, Andrew D.Journal of Enzyme Inhibition and Medicinal Chemistry (2007), 22 (5), 527-540CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)A review. The small and highly electroneg. fluorine atom can play a remarkable role in medicinal chem. Selective installation of fluorine into a therapeutic or diagnostic small mol. candidate can enhance a no. of pharmacokinetic and physicochem. properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a no. of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomog. (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chem. applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimize mol. properties.(i) Maienfisch, P.; Hall, R. G. The importance of fluorine in the life science industry. Chimia 2004, 58, 93– 99, DOI: 10.2533/000942904777678091[Crossref], [CAS], Google Scholar4ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjt1yisbs%253D&md5=0b770772370a49778e3927efc3ccd14cThe importance of fluorine in the life science industryMaienfisch, Peter; Hall, Roger G.Chimia (2004), 58 (3), 93-99CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)Fluorine-contg. compds. are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the no. of fluorinated org. mols. reaching com. status as crop protection products and pharmaceutical drugs has been obsd.: in 1978, ∼600 pesticides were known, but only approx. 25 (4%) contained fluorine. Today, fluorine-contg. compds. account for more than 17% of all com. available crop protection agents and many others are currently under development. The structures of the fluorine-contg. development compds. proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ∼8% of all synthetic drugs. Six years later already more than 1500 fluorine-contg. drugs were under development. Fluorine-contg. compds. have also been successful in the market-place, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac), Paroxetine (Paxil), Ciprofloxacin (Cipro) and Cisaprid (Propulsid). This success is mainly due to the fact that selectively fluorinated compds. can exhibit dramatically improved potency when compared to the non-fluorinated analogs. The incorporation of fluorine into a biol. active compd. alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chem. and metabolic stability, and the bioavailability. The pos. effects of fluorine on the biol. efficiency is outlined by three examples: in the chem. class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biol. activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem-difluorovinyl group results in a strong decrease of biol. activity. - 5(a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016, 116, 422– 518, DOI: 10.1021/acs.chemrev.5b00392[ACS Full Text.
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Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronol. and classified according to an assocn. with a particular clin. indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qual. conclusions in this article aim to promote innovative insights into drug development. - 6(a) Jeschke, P. The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem 2004, 5, 570– 589, DOI: 10.1002/cbic.200300833[Crossref], [CAS], Google Scholar.6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFeqtLw%253D&md5=1f684935456162dfcbccf8069a6fd397The unique role of fluorine in the design of active ingredients for modern crop protectionJeschke, PeterChemBioChem (2004), 5 (5), 570-589CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.(b) Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manage. Sci. 2010, 66, 10– 27, DOI: 10.1002/ps.1829[Crossref], [PubMed], [CAS], Google Scholar.6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFGrsb3K&md5=6c28bc5a824d268f64c33e05e9b63df8The unique role of halogen substituents in the design of modern agrochemicalsJeschke, PeterPest Management Science (2010), 66 (1), 10-27CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)A review. The past 30 years have witnessed a period of significant expansion in the use of halogenated compds. in the field of agrochem. research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochem. with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, esp. in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the no. of com. products contg. mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addn. to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochems. throughout the twenty-first century. A no. of these recently developed agrochem. candidates contg. halogen substituents represent novel classes of chem. compds. with new modes of action. However, the complex structure-activity relationships assocd. with biol. active mols. mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a mol. at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilization of halogens and their unique role in the design of modern agrochems., exemplified by various com. products from Bayer CropScience coming from different agrochem. areas. Copyright © 2009 Society of Chem. Industry.(c) Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16– 29, DOI: 10.1016/j.jfluchem.2014.06.014[Crossref], [CAS], Google Scholar.6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFCgu7%252FM&md5=7fe60bc6faa07bfd629833ce8911c488Successful fluorine-containing herbicide agrochemicalsFujiwara, Tomoya; O'Hagan, DavidJournal of Fluorine Chemistry (2014), 167 (), 16-29CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A review. Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-contg. compds. have made a significant contribution to the development of products for the agrochems. industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compds. are grouped by mode of action. A synthesis route is described for each compd. although the synthesis presented may not actually be the industrial process.(d) Jeschke, P. Latest generation of halogen-containing pesticides. Pest Manage. Sci. 2017, 73, 1053– 1056, DOI: 10.1002/ps.4540[Crossref], [PubMed], [CAS], Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjs1Oqsrw%253D&md5=ba3907b014cc806b92985351db88b1b0Latest generation of halogen-containing pesticidesJeschke, PeterPest Management Science (2017), 73 (6), 1053-1066CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)Agriculture is confronted with enormous challenges, from prodn. of enough high-quality food to water use, environmental impacts and issues combined with a continually growing world population. Modern agricultural chem. has to support farmers by providing innovative agrichems., used in applied agriculture. In this context, the introduction of halogen atoms into an active ingredient is still an important tool to modulate the properties of new crop protection compds. Since 2010, around 96% of the launched products (herbicides, fungicides, insecticides/acaricides and nematicides) contain halogen atoms. The launched nematicides contain the largest no. of halogen atoms, followed by insecticides/acaricides, herbicides and fungicides. In this context, fungicides and herbicides contain in most cases fluorine atoms, whereas nematicides and insecticides contain in most cases 'mixed' halogen atoms, for example chlorine and fluorine. This review gives an overview of the latest generation of halogen-contg. pesticides launched over the past 6 years and describes current halogen-contg. development candidates. © 2017 Society of Chem. Industry.
- 7(a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem., Int. Ed. 2013, 52, 8214– 8264, DOI: 10.1002/anie.201206566[Crossref], [CAS], Google Scholar.7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCrs7bI&md5=1dafdf60409a792e78d946731f6cc2b9Introduction of Fluorine and Fluorine-Containing Functional GroupsLiang, Theresa; Neumann, Constanze N.; Ritter, TobiasAngewandte Chemie, International Edition (2013), 52 (32), 8214-8264CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.(b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and tri-fluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015, 115, 826– 870, DOI: 10.1021/cr500277b .(c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules by transition metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 2015, 115, 931– 972, DOI: 10.1021/cr500257c .(d) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V. Polyfluorinated ethanes as versatile fluorinated C2-building blocks for organic synthesis. Chem. Rev. 2015, 115, 973– 1050, DOI: 10.1021/cr500465n[ACS Full Text.
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- 10(a) Park, K. B.; Kitteringham, N. R. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab. Rev. 1994, 26, 605– 643, DOI: 10.3109/03602539408998319[Crossref], [PubMed], [CAS], Google Scholar.10ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmslSqtbc%253D&md5=a766e575c62e197c3a03a4557273b9ddEffects of fluorine substitution on drug metabolism: Pharmacological and toxicological implicationsPark, B. Kevin; Kitteringham, Neil R.Drug Metabolism Reviews (1994), 26 (3), 605-43CODEN: DMTRAR; ISSN:0360-2532.A review with 112 refs. Physicochem. properties of fluorinated drugs, fluorine substitution effect on drug metab., and fluorinated compds. as enzyme inhibitors are discussed.(b) Murphy, C. D.; Sandford, G. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity. Expert Opin. Drug Metab. Toxicol. 2015, 11, 589– 599, DOI: 10.1517/17425255.2015.1020295[Crossref], [PubMed], [CAS], Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksFymt78%253D&md5=b5c542a9e9d7e3c246d4f24da4918f2bRecent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicityMurphy, Cormac D.; Sandford, GrahamExpert Opinion on Drug Metabolism & Toxicology (2015), 11 (4), 589-599CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: Fluorine's unique physicochem. properties make it a key element for incorporation into pharmacol. active compds. Its presence in a drug can alter a no. of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailability and how the effects obsd. are related to the physicochem. characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biol. systems for fluorinated drug prodn. is discussed. Expert opinion: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technol. for the manufg. scale and new reagents and methods are required to meet the demands for the prepn. of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to det. the nature of transformation products that may cause ecol. damage.
- 11(a) Meanwell, N. A. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem. Res. Toxicol. 2011, 24, 1420– 1456, DOI: 10.1021/tx200211v[ACS Full Text.
], [CAS], Google Scholar11ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptlCitLs%253D&md5=9ddcf6dc81bf8ab0441df5037979ff4eImproving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and SafetyMeanwell, Nicholas A.Chemical Research in Toxicology (2011), 24 (9), 1420-1456CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. The development of small mol. drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclin. profiling that have improved compd. triaging and altered the underlying reasons for compd. attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochem. properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by mols. with increased mol. wt. and higher overall lipophilicity. The preponderance of mols. expressing these properties is frequently a function of increased arom. ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochem. properties assocd. with marketed drugs, guidelines for drug design have been developed that are based largely on calcd. parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochem. properties of a mol. that are consistent with the potential for good oral absorption were initially defined by Lipinski, with addnl. insights allowing further refinement, while deeper analyses have explored the correlation with metabolic stability and toxicity. These insights have been augmented by careful analyses of physicochem. aspects of drug-target interactions, with thermodn. profiling indicating that the signature of best-in-class drugs is a dependence on enthalpy to drive binding energetics rather than entropy, which is dependent on lipophilicity. Optimization of the entropic contribution to the binding energy of a ligand to its target is generally much easier than refining the enthalpic element. Consequently, in the absence of a fundamental understanding of the thermodn. complexion of an interaction, the design of mols. with increased lipophilicity becomes almost inevitable. The application of ligand efficiency, a measure of affinity per heavy atom, group efficiency, which assesses affinity in the context of structural changes, and lipophilic ligand efficiency, which relates potency to lipophilicity, offer less sophisticated but practically useful anal. algorithms to assess the quality of drug-target interactions. These parameters are readily calcd. and can be applied to lead optimization programs in a fashion that helps to maximize potency while minimizing the kind of lipophilic burden that has been dubbed "mol. obesity". Several recently described lead optimization campaigns provide illustrative, informative, and productive examples of the effect of paying close attention to carefully controlling physicochem. properties by monitoring ligand efficiency and lipophilic ligand efficiency. However, to be successful during the lead optimization phase, drug candidate identification programs will need to adopt a holistic approach that integrates multiple parameters, many of which will have unique dependencies on both the drug target and the specific chemotype under prosecution. Nevertheless, there are many important drug targets that necessitate working in space beyond that which has been defined by the retrospective analyses of marketed drugs and which will require adaptation of some of the guideposts that are useful in directing lead optimization.(b) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564– 616, DOI: 10.1021/acs.chemrestox.6b00043[ACS Full Text
], [CAS], Google Scholar11bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVCrs7Y%253D&md5=aef48399fb698b5f958c1cc11e1d25aaImproving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug SpaceMeanwell, Nicholas A.Chemical Research in Toxicology (2016), 29 (4), 564-616CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The phys., biol., and toxicol. properties of a drug candidate are inextricably linked to its structure, and once a mol. has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biol. properties of a mol. from an anal. of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a mol. is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clin. trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective anal. of drug design practices over the past decade has focused attention on the perception that contemporary mols. are unnecessarily obese, burdened by high mol. wt. and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chem. community with practical guideposts to enhancing compd. quality in the drug design phase and which can readily be applied, a series of efficiency indexes have been proposed that attempt to define aspects of compd. quality in the context of a series of physicochem. parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a mol. on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compd. aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, mols. that fall into space beyond that assocd. with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clin. therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compd. quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success. - 12Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455[ACS Full Text
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- 17Shaughnessy, M. J.; Harsanyi, A.; Li, J.; Bright, T.; Murphy, C. D.; Sandford, G. Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life. ChemMedChem 2014, 9, 733– 736, DOI: 10.1002/cmdc.201300490
- 18Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-guided drug design. MedChemComm 2013, 4, 631– 652, DOI: 10.1039/c2md20317k[Crossref], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkslWmur0%253D&md5=61c667aa6f5c24de3fe110f384f323bdMetabolism-guided drug designStepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.MedChemComm (2013), 4 (4), 631-652CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. Preclin. drug metab. studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chem. entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns assocd. with the formation of protein and/or DNA-reactive metabolites. Metab. studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compds. with increased resistance to metab. and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metab. studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P 450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small mol. drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chem. intervention strategies. This review will showcase case studies of metab.-guided drug design using literature and inhouse examples.
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- 20(a) Stalford, A. C.; Maggs, J. L.; Gilchrist, T. L.; Park, B. K. The metabolism of 16-fluoroestradiols in vivo: chemical strategies for restricting the oxidative biotransformations of an estrogen receptor imaging agent. Steroids 1997, 62, 750– 776, DOI: 10.1016/S0039-128X(97)00116-5 .(b) Diana, G. D.; Rudewicz, P.; Pevear, D. C.; Nitz, T. J.; Aldous, S. C.; Aldous, D. J.; Robinson, D. T.; Draper, T.; Dutko, F. J.; Aldi, C.; Gendron, G.; Oglesby, R. C.; Volkots, D. L.; Reurnan, M.; Bailey, T. R.; Czerniak, R.; Block, T.; Roland, R.; Oppermand, J. Picornavirus inhibitors: trifluoromethyl substitution provides a global protective effect against hepatic metabolism. J. Med. Chem. 1996, 38, 1355– 1371, DOI: 10.1021/jm00008a014 .(c) DeGoey, D. A.; Chen, H.-J.; Cox, P. B.; Wendt, M. D. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J. Med. Chem. 2017, DOI: 10.1021/acs.jmedchem.7b00717
- 21(a) Ojima, I. Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies. J. Fluorine Chem. 2017, 198, 10– 23, DOI: 10.1016/j.jfluchem.2016.12.016[Crossref], [PubMed], [CAS], Google Scholar.21ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlGntw%253D%253D&md5=b421b53c8371829b4ca44bbec7980a0eStrategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studiesOjima, IwaoJournal of Fluorine Chemistry (2017), 198 (), 10-23CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chem. and chem. biol. studies. Novel 3'-difluorovinyltaxoids were strategically designed to block the metab. by cytochrome P 450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3'-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3'-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymn. assay, morphol. anal. by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR anal. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other anal. methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean anal. of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical soln. to this problem.(b) Kuznetsova, L.; Sun, L.; Chen, J.; Zhao, X.; Seitz, J.; Das, M.; Li, Y.; Veith, J. M.; Pera, P.; Bernacki, R. J.; Xia, S.; Horwitz, S. B.; Ojima, I. Synthesis and biological evaluation of novel 3′-difluorovinyl toxoids. J. Fluorine Chem. 2012, 143, 177– 188, DOI: 10.1016/j.jfluchem.2012.07.007[Crossref], [PubMed], [CAS], Google Scholar.21bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyku7bI&md5=175149f9c565c30d1eccbeeaad4c3f75Synthesis and biological evaluation of novel 3'-difluorovinyl taxoidsKuznetsova, Larissa; Sun, Liang; Chen, Jin; Zhao, Xianrui; Seitz, Joshua; Das, Manisha; Li, Yuan; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.; Xia, Shujun; Horwitz, Susan B.; Ojima, IwaoJournal of Fluorine Chemistry (2012), 143 (), 177-188CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A series of 3'-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metab. by cytochrome P 450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3'-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the crit. importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H < F < Cl < N3. Among the twenty five 3'-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymn. much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymn., indicating strong stabilization of microtubules. Mol. modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.(c) Ehrlichová, M.; Ojima, I.; Chen, J.; Václavíková, R.; Němcová-Fürstová, V.; Vobořilová, J.; Šimek, P.; Horský, S.; Souček, P.; Kovář, J.; Brabec, M.; Gut, I. Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 2012, 385, 1035– 1048, DOI: 10.1007/s00210-012-0785-4[Crossref], [PubMed], [CAS], Google Scholar21chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSgsL3M&md5=0fcb97f2eeead6bb7bb18902a7dfc30cTransport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cellsEhrlichova, Marie; Ojima, Iwao; Chen, Jin; Vaclavikova, Radka; Nemcova-Fuerstova, Vlasta; Voborilova, Jana; Simek, Petr; Horsky, Stanislav; Soucek, Pavel; Kovar, Jan; Brabec, Marek; Gut, IvanNaunyn-Schmiedeberg's Archives of Pharmacology (2012), 385 (10), 1035-1048CODEN: NSAPCC; ISSN:0028-1298. (Springer)Resistance of tumors to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumor uptake of taxanes and their rapid metab. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metab. and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metab. of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metab. of the novel taxanes which was therefore not responsible for their different sensitivity, the obsd. differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G2/M block of the cell cycle similar to paclitaxel, but lower at concns. by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumor cells.
- 22Mascitti, V.; Stevens, B. D.; Choi, C.; McClure, K. F.; Guimarães, C. R. W.; Farley, K. A.; Munchhof, M. J.; Robinson, R. P.; Futatsugi, K.; Lavergne, S. Y.; Lefker, B.; Cornelius, A. P.; Bonin, P. D.; Kalgutkar, A. S.; Sharma, R.; Chen, Y. Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 1306– 1309, DOI: 10.1016/j.bmcl.2011.01.088
- 23Barnes-Seeman, D.; Beck, J.; Springer, C. Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analysis. Curr. Top. Med. Chem. 2014, 14, 855– 864, DOI: 10.2174/1568026614666140202204242[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlt1WntbY%253D&md5=214858abeb71f16981842708115ddb61Fluorinated Compounds in Medicinal Chemistry: Recent Applications, Synthetic Advances and Matched-Pair AnalysesBarnes-Seeman, David; Beck, Jeremy; Springer, ClaytonCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (7), 855-864CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. In recent years, several new fluorinated functional groups have been employed in medicinal chem. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-contg. groups. In addn., we examine the application of some fluorinated functional groups that have recently been gaining popularity in drug discovery. We use matched-pair anal. to assemble aggregate data on the impact on potency of one of these groups, pentafluorosulfanyl, as compared to trifluoromethyl. We further used matchedpair anal. to identify some interesting effects on in vitro ADME properties of replacing H by F on certain moieties.
- 24Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.-H.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically stable tert-butyl replacement. ACS Med. Chem. Lett. 2013, 4, 514– 516, DOI: 10.1021/ml400045j[ACS Full Text
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- 28Liu, G.; Abraham, S.; Liu, X.; Xu, S.; Rooks, A. M.; Nepomuceno, R.; Dao, A.; Brigham, D.; Gitnick, D.; Insko, D. E.; Gardner, M. F.; Zarrinkar, P. P.; Christopher, R.; Belli, B.; Armstrong, R. C.; Holladay, M. W. Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 3436– 3441, DOI: 10.1016/j.bmcl.2015.07.023[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOktL7I&md5=e0af0933baacfafe789ab3f49aa26f55Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitorsLiu, Gang; Abraham, Sunny; Liu, Xing; Xu, Shimin; Rooks, Allison M.; Nepomuceno, Ron; Dao, Alan; Brigham, Daniel; Gitnick, Dana; Insko, Darren E.; Gardner, Michael F.; Zarrinkar, Patrick P.; Christopher, Ron; Belli, Barbara; Armstrong, Robert C.; Holladay, Mark W.Bioorganic & Medicinal Chemistry Letters (2015), 25 (17), 3436-3441CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Based on a putative binding mode of quizartinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clin. development, the authors have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compd. I in tumor xenograft model for further preclin. development.
- 29Sebhat, I. K.; Franklin, C.; Lo, M. M.-C.; Chen, D.; Jewell, J. P.; Miller, R.; Pang, J.; Palyha, O.; Kan, Y.; Kelly, T. M.; Guan, X.-M.; Marsh, D. J.; Kosinski, J. A.; Metzger, J. M.; Lyons, K.; Dragovic, J.; Guzzo, P. R.; Henderson, A. J.; Reitman, M. L.; Nargund, R. P.; Wyvratt, M. J.; Lin, L. S. Discovery of MK-5046, a potent, selective bombesin receptor subtype-3 agonist for the treatment of obesity. ACS Med. Chem. Lett. 2011, 2, 43– 47, DOI: 10.1021/ml100196d[ACS Full Text
], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht12lt7fK&md5=5c50e792b9a560ca33da2e9392a12ae1Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of ObesitySebhat, Iyassu K.; Franklin, Christopher; Lo, Michael M.-C.; Chen, David; Jewell, James P.; Miller, Randy; Pang, Jianmei; Palyha, Oksana; Kan, Yanqing; Kelly, Theresa M.; Guan, Xiao-Ming; Marsh, Donald J.; Kosinski, Jennifer A.; Metzger, Joseph M.; Lyons, Kathryn; Dragovic, Jasminka; Guzzo, Peter R.; Henderson, Alan J.; Reitman, Marc L.; Nargund, Ravi P.; Wyvratt, Matthew J.; Lin, Linus S.ACS Medicinal Chemistry Letters (2011), 2 (1), 43-47CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the development and characterization of compd. 22 (MK-5046), a potent, selective small mol. agonist of BRS-3 (bombesin receptor subtype-3). In pharmacol. testing using diet-induced obese mice, compd. 22 caused mechanism-based, dose-dependent redns. in food intake and body wt. - 30Furet, P.; Guagnano, V.; Fairhurst, R. A.; Imbach-Weese, P.; Bruce, I.; Knapp, M.; Fritsch, C.; Blasco, F.; Blanz, J.; Aichholz, R.; Hamon, J.; Fabbro, D.; Caravatti, G. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 2013, 23, 3741– 3748, DOI: 10.1016/j.bmcl.2013.05.007[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosFaisrY%253D&md5=a0d2d69e01e7a82a5fed04114105925eDiscovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluationFuret, Pascal; Guagnano, Vito; Fairhurst, Robin A.; Imbach-Weese, Patricia; Bruce, Ian; Knapp, Mark; Fritsch, Christine; Blasco, Francesca; Blanz, Joachim; Aichholz, Reiner; Hamon, Jacques; Fabbro, Doriano; Caravatti, GiorgioBioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3741-3748CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compds. in inhibiting PI3Kα, a medicinal chem. program has led to the discovery of the clin. candidate NVP-BYL719 I.
- 31(a) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A survey of the role of noncovalent sulfur interactions in drug design. J. Med. Chem. 2015, 58, 4383– 4438, DOI: 10.1021/jm501853m[ACS Full Text.
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], [CAS], Google Scholar31bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFart7rI&md5=7192e3b57e66fc6eb9dd53165427d449Intermolecular Sulfur···Oxygen Interactions: Theoretical and Statistical InvestigationsZhang, Xuejin; Gong, Zhen; Li, Jian; Lu, TaoJournal of Chemical Information and Modeling (2015), 55 (10), 2138-2153CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Intermol. S···O interactions are very common and are important in biol. systems, but until recently, the presence of these contacts in protein-ligand systems largely depended on serendipitous discovery instead of rational design. Here we provide insight into the phenomenon of intermol. S···O contacts by focusing on three sulfur-contg. arom. rings. Quantum mechanics is employed to characterize the strength and directionality of the S···O interactions and to det. their energy dependence on their geometric parameters. Protein Data Bank mining is performed to systematically det. the occurrence and geometry of intermol. S···O interactions, and several representative examples are discussed. Three typical cases are investigated using a combined quantum mechanics/mol. mechanics approach to demonstrate the potential of these interactions in improving binding affinities and physiochem. properties. Overall, our work elucidates the structures and energy features of intermol. S···O interactions and addresses their use in mol. design. - 32Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B. T.; Lai, A. G.; Setti, E.; Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L.; Struss, B.; Gibney, M.; Armstrong, R. C.; Gunawardane, R. N.; Nepomuceno, R. R.; Valenta, I.; Hua, H.; Gardner, M. F.; Cramer, M. D.; Gitnick, D.; Insko, D. E.; Apuy, J. L.; Jones-Bolin, S.; Ghose, A. K.; Herbertz, T.; Ator, M. A.; Dorsey, B. D.; Ruggeri, B.; Williams, M.; Bhagwat, S.; James, J.; Holladay, M. W. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J. Med. Chem. 2012, 55, 1082– 1105, DOI: 10.1021/jm2009925
- 33Pettersson, M.; Johnson, D. S.; Humphrey, J. M.; Butler, T. W.; am Ende, C. W.; Fish, B. A.; Green, M. E.; Kauffman, G. W.; Mullins, P. B.; O’Donnell, C. J.; Stepan, A. F.; Stiff, C. M.; Subramanyam, C.; Tran, T. P.; Cooper Vetelino, B.; Yang, E.; Xie, L.; Bales, K. R.; Pustilnik, L. R.; Steyn, S. J.; Wood, K. M.; Verhoest, P. R. Design of pyridopyrazine-1,6-dione γ-secretase modulators that align potency, MDR efflux ratio, and metabolic stability. ACS Med. Chem. Lett. 2015, 6, 596– 601, DOI: 10.1021/acsmedchemlett.5b00070[ACS Full Text
], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVaksrg%253D&md5=ba402f2e67fd9500123cbc7b215d3361Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic StabilityPettersson, Martin; Johnson, Douglas S.; Humphrey, John M.; Butler, Todd W.; am Ende, Christopher W.; Fish, Benjamin A.; Green, Michael E.; Kauffman, Gregory W.; Mullins, Patrick B.; O'Donnell, Christopher J.; Stepan, Antonia F.; Stiff, Cory M.; Subramanyam, Chakrapani; Tran, Tuan P.; Vetelino, Beth Cooper; Yang, Eddie; Xie, Longfei; Bales, Kelly R.; Pustilnik, Leslie R.; Steyn, Stefanus J.; Wood, Kathleen M.; Verhoest, Patrick R.ACS Medicinal Chemistry Letters (2015), 6 (5), 596-601CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochem. properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp3-character. The lead compd. I (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust redns. of brain Aβ42 and Aβ40 were obsd. in a guinea pig time-course expt. - 34Mukherjee, P.; Pettersson, M.; Dutra, J. K.; Xie, L.; am Ende, C. W. Trifluoromethyl oxetanes: synthesis and evaluation as a tert-butyl isostere. ChemMedChem 2017, 12, 1574– 1577, DOI: 10.1002/cmdc.201700333[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2jur%252FJ&md5=fec9231daeaa93fcf67e63cd74815060Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl IsostereMukherjee, Paramita; Pettersson, Martin; Dutra, Jason K.; Xie, Longfei; am Ende, Christopher W.ChemMedChem (2017), 12 (19), 1574-1577CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The synthesis of new trifluoromethyl oxetanes such as I [R = 4-CO2HC6H4, 2-MeOC6H4CH2, 5-CO2Et-2-thienyl, etc.] was developed using Corey-Chaykovsky epoxidn./ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displayed a broad substrate scope. A limitation to the epoxidn./ring expansion was obsd. when attempting to use a more sterically encumbered aryl trifluoromethyl ketone, the intermediate epoxide, 2-(trifluoromethyl)-2-(2,4,6-trimethylphenyl)oxirane was isolated. The trifluoromethyl oxetane was also evaluated as a tert-Bu isostere in the context of the γ-secretase modulator (GSM) program. The trifluoromethyl oxetane-contg. GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-Bu GSM analog was demonstrated, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-Bu isostere.
- 35(a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2005, 48, 141– 151, DOI: 10.1021/jm0493156[ACS Full Text.
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(American Chemical Society)A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (I) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclin. species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of I, was selected for development as a potential new treatment for type 2 diabetes.(b) Kim, D.; Kowalchick, J.E.; Edmondson, S. D.; Mastracchio, A.; Xu, J.; Eiermann, G. J.; Leiting, B.; Wu, J. K.; Pryor, K. D.; Patel, R. A.; He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate). Bioorg. Med. Chem. Lett. 2007, 17, 3373– 3377, DOI: 10.1016/j.bmcl.2007.03.098 .(c) Thornberry, N. A.; Weber, A. E. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr. Top. Med. Chem. 2007, 7, 557– 568, DOI: 10.2174/156802607780091028[Crossref], [PubMed], [CAS], Google Scholar35chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsFersrY%253D&md5=8221de915c797c517f6116acb9c03cd1Discovery of JANUVIA (sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetesThornberry, Nancy A.; Weber, Ann E.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2007), 7 (6), 557-568CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclin. validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compds. inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclin. species. Indeed, the obsd. toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chem. efforts focused on identifying a highly selective DPP-4 inhibitor for clin. development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivs. were prepd., culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclin. species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes. - 36Mayer, S. C.; Kreft, A. F.; Harrison, B.; Abou-Gharbia, M.; Antane, M.; Aschmies, S.; Atchison, K.; Chlenov, M.; Cole, D. C.; Comery, T.; Diamantidis, G.; Ellingboe, J.; Fan, K.; Galante, R.; Gonzales, C.; Ho, D. M.; Hoke, M. E.; Hu, Y.; Huryn, D.; Jain, U.; Jin, M.; Kremer, K.; Kubrak, D.; Lin, M.; Lu, P.; Magolda, R.; Martone, R.; Moore, W.; Oganesian, A.; Pangalos, M. N.; Porte, A.; Reinhart, P.; Resnick, L.; Riddell, D. R.; Sonnenberg-Reines, J.; Stock, J. R.; Sun, S.-C.; Wagner, E.; Wang, T.; Woller, K.; Xu, Z.; Zaleska, M. M.; Zeldis, J.; Zhang, M.; Zhou, H.; Jacobsen, J. S. Discovery of begacestat, a notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer’s disease. J. Med. Chem. 2008, 51, 7348– 7351, DOI: 10.1021/jm801252w[ACS Full Text
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- 38Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.; Claremon, D. A.; Elliott, J. M.; Freidinger, R. M.; King, S. A.; Libby, B. E.; McIntyre, C. J.; Pribush, D. A.; Remy, D. C.; Smith, G. R.; Tebben, A. J.; Jurkiewicz, N. K.; Lynch, J. J.; Salata, J. J.; Sanguinetti, M. C.; Siegl, P. K. S.; Slaughter, D. E.; Vyas, K. Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current IKs by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide. J. Med. Chem. 1997, 40, 3865– 3868, DOI: 10.1021/jm970517u
- 39(a) Tohnishi, M.; Nishimatsu, T.; Motoba, K.; Hirooka, T.; Seo, A. Development of a novel insecticide, flubendiamide. J. Pestic. Sci. 2010, 35, 490– 491, DOI: 10.1584/jpestics.J10-06[Crossref], [CAS], Google Scholar.39ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvFentA%253D%253D&md5=c30fd345f321bd82fc74a97143a0debcDevelopment of a novel insecticide, flubendiamideTohnishi, Masanori; Nishimatsu, Tetsuyoshi; Motoba, Kazuhiko; Hirooka, Takashi; Akira, SeoJournal of Pesticide Science (Tokyo, Japan) (2010), 35 (4), 490-491, 508-515CODEN: JPSTCF; ISSN:1348-589X. (Pesticide Science Society of Japan)Flubendiamide, a novel class insecticide possessing a unique chem. structure, was discovered by Nihon Nohyaku Co., Ltd., and was registered in Japan in 2007 under the trade name of Phoenix WDG. The compd. is not only the first example of 1,2-benzenedicarboxamide insecticides but also the first practical synthetic insecticide with a mode of action as an activator of ryanodine receptors. It shows high and selective activity against lepidopterous insect pests, which leads to excellent efficacy in the field and excellent safety against non-target organisms, including various beneficial arthropods and natural enemies. These properties suggested the suitability of flubendiamide for integrated pest management (IPM) programs.(b) Nakao, T.; Banba, S. Broflanilide: a meta-diamide insecticide with a novel mode of action. Bioorg. Med. Chem. 2016, 24, 372– 377, DOI: 10.1016/j.bmc.2015.08.008[Crossref], [PubMed], [CAS], Google Scholar39bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVajsrzN&md5=4e4ee18a96c5e975e623b8bc7d058ce9Broflanilide: A meta-diamide insecticide with a novel mode of actionNakao, Toshifumi; Banba, ShinichiBioorganic & Medicinal Chemistry (2016), 24 (3), 372-377CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A review. Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil. It has been proposed that the site of action for desmethyl-broflanilide is close to G336 in the M3 region of the Drosophila RDL GABA receptor. However, although the site of action for desmethyl-broflanilide appears to overlap with that of macrocyclic lactones, different modes of actions have been demonstrated for desmethyl-broflanilide and the macrocyclic lactones. The mechanisms underlying the high selectivity of meta-diamides are also discussed in this review. Broflanilide is expected to become a prominent insecticide because it is effective against pests with resistance to cyclodienes and fipronil.
- 40Swaminathan, S.; Siddiqui, A. U.; Pinkerton, F. D.; Gerst, N.; Wilson, W. K.; Schroepfer, G. J. Inhibitors of sterol synthesis: 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholestan-15-one, an analog of a potent hypocholesterolemic agent in which its major metabolism is blocked. Biochem. Biophys. Res. Commun. 1994, 201, 168– 173, DOI: 10.1006/bbrc.1994.1684
- 41Lepri, S.; Goracci, L.; Valeri, A.; Cruciani, G. Metabolism study and biological evaluation of bosentan derivatives. Eur. J. Med. Chem. 2016, 121, 658– 670, DOI: 10.1016/j.ejmech.2016.06.006[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVWltL%252FO&md5=c434e8c19b0dcb90af6ba73696388b0bMetabolism study and biological evaluation of bosentan derivativesLepri, Susan; Goracci, Laura; Valeri, Aurora; Cruciani, GabrieleEuropean Journal of Medicinal Chemistry (2016), 121 (), 658-670CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P 450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogs are often designed to block the major sites of metab. In this paper bosentan analogs were synthesized, and their metab. and biol. activity were evaluated. All synthesized compds. showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
- 42(a) Thangavelu, B.; Bhansali, P.; Viola, R. E. Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors. Bioorg. Med. Chem. 2015, 23, 6622– 6631, DOI: 10.1016/j.bmc.2015.09.017 .(b) Thangavelu, B.; Mutthamsetty, V.; Wang, Q.; Viola, R. E. Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease. Bioorg. Med. Chem. 2017, 25, 870– 885, DOI: 10.1016/j.bmc.2016.11.060[Crossref], [PubMed], [CAS], Google Scholar42bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFWlsb%252FJ&md5=a22f8d86c7e49d155bfcf87ddc3cdf85Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan diseaseThangavelu, Bharani; Mutthamsetty, Vinay; Wang, Qinzhe; Viola, Ronald E.Bioorganic & Medicinal Chemistry (2017), 25 (3), 870-885CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Canavan disease is a fatal neurol. disorder caused by defects in the metab. of N-acetyl-L-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA obsd. in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-assocd. enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examd. (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and sol. form of ANAT the authors can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compd. libraries. Two core structures of these moderate binding compds. have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition consts. (Ki values) against ANAT. Slowing the prodn. of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
- 43Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 3920– 3928, DOI: 10.1021/jm960444z
- 44(a) Rose, T. E.; Morisseau, C.; Liu, J.-Y.; Inceoglu, B.; Jones, P. D.; Sanborn, J. R.; Hammock, B. D. 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain. J. Med. Chem. 2010, 53, 7067– 7075, DOI: 10.1021/jm100691c[ACS Full Text.
], [CAS], Google Scholar44ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWlsb%252FL&md5=bc2b151553d732942c1ac7e2e963d5241-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure-Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory PainRose, Tristan E.; Morisseau, Christophe; Liu, Jun-Yan; Inceoglu, Bora; Jones, Paul D.; Sanborn, James R.; Hammock, Bruce D.Journal of Medicinal Chemistry (2010), 53 (19), 7067-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine sol. epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analog 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea. This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mech. withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.(b) Lee, K. S. S.; Liu, J.-Y.; Wagner, K. M.; Pakhomova, S.; Dong, H.; Morisseau, C.; Fu, S. H.; Yang, J.; Wang, P.; Ulu, A.; Mate, C. A.; Nguyen, L. V.; Hwang, S. H.; Edin, M. L.; Mara, A. A.; Wulff, H.; Newcomer, M. E.; Zeldin, D. C.; Hammock, B. D. Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. J. Med. Chem. 2014, 57, 7016– 7030, DOI: 10.1021/jm500694p[ACS Full Text
], [CAS], Google Scholar44bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Git77K&md5=1f57ad6909389ac8d101fb548b64c2e2Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo EfficacyLee, Kin Sing Stephen; Liu, Jun-Yan; Wagner, Karen M.; Pakhomova, Svetlana; Dong, Hua; Morisseau, Christophe; Fu, Samuel H.; Yang, Jun; Wang, Peng; Ulu, Arzu; Mate, Christina A.; Nguyen, Long V.; Hwang, Sung Hee; Edin, Matthew L.; Mara, Alexandria A.; Wulff, Heike; Newcomer, Marcia E.; Zeldin, Darryl C.; Hammock, Bruce D.Journal of Medicinal Chemistry (2014), 57 (16), 7016-7030CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of sol. epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, the authors describe a series of newly synthesized sEH inhibitors I [R1 = 4-CF3C6H4, 4-CF3OC6H4; (CF3)2CFC6H4, etc.; R2 = MeCO, MeCH2CO, MeCH2CH2CO, etc.] with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better phys. properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans. - 45Atouioual, B.; Hagmann, L.; Jung, P. M. J.; Lamy, E.; Winkler, T. Atropisomerism about a heptafluoroisopropyl to aryl bond in 5-amino-4-heptafluoroisopropyl indazole. Tetrahedron Lett. 2008, 49, 5403– 5404, DOI: 10.1016/j.tetlet.2008.07.006
- 46(a) Dieckhaus, C. M.; Thompson, C. D.; Roller, S. G.; Macdonald, T. L. Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem.-Biol. Interact. 2002, 142, 99– 117, DOI: 10.1016/S0009-2797(02)00057-1[Crossref], [PubMed], [CAS], Google Scholar.46ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotVKrt78%253D&md5=ade528b1c851e1bf204984d1ae9cf957Mechanisms of idiosyncratic drug reactions: the case of FelbamateDieckhaus, Christine M.; Thompson, Charles D.; Roller, Shane G.; MacDonald, Timothy L.Chemico-Biological Interactions (2002), 142 (1-2), 99-117CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)A review. Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence, and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicol. outcome. As the name implies, IDR are unpredictable and often result in the post-marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include Trovafloxacin, Zileuton, Troglitazone, Tolcapone, and Felbamate. To date there exists no pre-clin. model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, the authors have studied the IDR assocd. with a model compd., Felbamate. The studies with Felbamate are consistent with the theory that compds. which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In addn., the data suggest that under normal physiol. conditions glutathione plays a protective role in preventing IDR during Felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clin. studies with Felbamate have been able to demonstrate an assocn. between reactive metabolite formation and a clin. relevant toxicity; however, addnl. research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.(b) Kapetanovic, I. M.; Torchin, C. D.; Strong, J. M.; Yonekawa, W. D.; Lu, C.; Li, A. P.; Dieckhaus, C. M.; Santos, W. L.; Macdonald, T. L.; Sofia, R. D.; Kupferberg, H. J. Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem.-Biol. Interact. 2002, 142, 119– 134, DOI: 10.1016/S0009-2797(02)00058-3[Crossref], [PubMed], [CAS], Google Scholar.46bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotVKrt7w%253D&md5=ca2ca0812084df77f02f42807c9a5372Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitroKapetanovic, Izet M.; Torchin, Cynthia D.; Strong, John M.; Yonekawa, Wayne D.; Lu, Chuang; Li, Albert P.; Dieckhaus, Christine M.; Santos, Webster L.; MacDonald, Timothy L.; Sofia, R. Duane; Kupferberg, Harvey J.Chemico-Biological Interactions (2002), 142 (1-2), 119-134CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia assocd. with its use. It was proposed that a bioactivation of FBM leading to formation of α,β-unsatd. aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities assocd. with the parent drug. Other members of this class of compds., acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examd. effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metab. and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metab. of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concns. of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as obsd. with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metab. and/or metab. of other endogenous or exogenous compds. and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with crit. cellular macromols. or indirect interference with cellular detoxification mechanisms.(c) Popović, M.; Nierkens, S.; Pieters, R.; Uetrecht, J. Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem. Res. Toxicol. 2004, 17, 1568– 1576, DOI: 10.1021/tx0498197
- 47Parker, R. J.; Hartman, N. R.; Roecklein, B. A.; Mortko, H.; Kupferberg, H. J.; Stables, J.; Strong, J. M. Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by post-mitochondrial suspensions. Chem. Res. Toxicol. 2005, 18, 1842– 1848, DOI: 10.1021/tx050130r
- 48(a) Kupferberg, H. J.; Macdonald, T. L.; Dieckhaus, C. M.; Perhach, J. L.; Sofia, R. D. Fluorofelbamate: pharmacodynamic and metabolic profile of a potent anticonvulsant. Epilepsia 2000, 41 (Suppl 7), 214.(b) Mazarati, A. M.; Sofia, R. D.; Wasterlain, C. G. Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus. Seizure 2002, 11, 423– 430, DOI: 10.1053/seiz.2002.0677[Crossref], [PubMed], [CAS], Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38vnsFyhsQ%253D%253D&md5=95ecc59ab7d7bc7f320d1fb18c53f678Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticusMazarati Andrey M; Sofia R Duane; Wasterlain Claude GSeizure (2002), 11 (7), 423-30 ISSN:1059-1311.PURPOSE: To examine the seizure-protective properties of fluorofelbamate, a felbamate analog, on acute and chronic seizures in an experimental model of self-sustaining status epilepticus (SSSE). METHODS: SSSE was induced by stimulation of the perforant path for 30 min (PPS) through chronically implanted electrodes in free-running adult male Wistar rats. Fluorofelbamate was injected intravenously (i.v.) either 10 min, or 40 min after SSSE induction. Seizure and spike profiles were analyzed off-line. RESULTS: Fluorofelbamate injected during the early stages of SSSE (10 min after the end of PPS), shortened the duration of seizures in a dose-dependent manner. While a dose of 50 mg kg(-1) was ineffective, 100 and 200 mg kg(-1) reduced cumulative seizure time from 393 +/- 10 min to 15 +/- 8 min and 2.4 +/- 0.5 min respectively. Administration of fluorofelbamate (200 and 300 mg kg (-1)) at a late stage of SSSE, which is refractory to treatment with conventional anticonvulsants, also significantly attenuated seizures. Acute fluorofelbamate treatment (200 mg kg(-1) 10 min after PPS) significantly decreased the frequency of spontaneous seizures which follow SSSE after a 'latent' interval. Moreover, in contrast to control animals, fluorofelbamate-treated rats showed regression of spontaneous seizures, and an apparent remission of epilepsy within 2 months after SSSE. CONCLUSIONS: Acute treatment of SSSE with fluorofelbamate showed strong anticonvulsant effects even during the late stages of SSSE. In this model, it also displayed antiepileptogenic properties: it reduced the severity of chronic epilepsy after SSSE and lead to apparent remissions of that epilepsy.
- 49(a) Roecklein, B. A.; Sacks, H. J.; Mortko, H.; Stables, J. Fluorofelbamate. Neurotherapeutics 2007, 4, 97– 101, DOI: 10.1016/j.nurt.2006.11.015[Crossref], [PubMed], [CAS], Google Scholar.49ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXisFaksLk%253D&md5=24365b8c44f2be9837ac64ede8dca327Fluoro0felbamateRoecklein, Bryan A.; Sacks, Harry J.; Mortko, Henry; Stables, JamesNeurotherapeutics (2007), 4 (1), 97-101CODEN: NEURNV; ISSN:1933-7213. (Elsevier)A review. The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clin. studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was obsd. after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (Med-Pointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metab. that has demonstrated, in vitro, to avoid the prodn. of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.(b) Bialer, M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin. Invest. Drugs 2006, 15, 637– 647, DOI: 10.1517/13543784.15.6.637
- 50Xu, S.; Zhu, B.; Teffera, Y.; Pan, D. E.; Caldwell, C. G.; Doss, G.; Stearns, R. A.; Evans, D. C.; Beconi, M. G. Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes. Drug Metab. Dispos. 2005, 33, 121– 130, DOI: 10.1124/dmd.104.001842[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltlensg%253D%253D&md5=2422da6be675647a96f6b76ab1e88a84Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomesXu, Shiyao; Zhu, Bing; Teffera, Yohannes; Pan, Deborah E.; Caldwell, Charles G.; Doss, George; Stearns, Ralph A.; Evans, David C.; Beconi, Maria G.Drug Metabolism and Disposition (2005), 33 (1), 121-130CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-{[(4-trifluoromethoxyphenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1-(trans-4-{[(2,4-difluorophenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride (MRL-A and MRL-B), contg. a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compds. to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addn. of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chem. reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping expts. with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidn. and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16α-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, resp.). Herein, the authors describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.
- 51(a) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.; Harper, B.; Park, Y. J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J.K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E. (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2006, 49, 3614– 3627, DOI: 10.1021/jm060015t[ACS Full Text.
], [CAS], Google Scholar51ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslKht7Y%253D&md5=6ebe737acc317676ca1c7e4178d9719f(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide: A selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetesEdmondson, Scott D.; Mastracchio, Anthony; Mathvink, Robert J.; He, Jiafang; Harper, Bart; Park, You-Jung; Beconi, Maria; Di Salvo, Jerry; Eiermann, George J.; He, Huaibing; Leiting, Barbara; Leone, Joseph F.; Levorse, Dorothy A.; Lyons, Kathryn; Patel, Reshma A.; Patel, Sangita B.; Petrov, Aleksandr; Scapin, Giovanna; Shang, Jackie; Roy, Ranabir Sinha; Smith, Aaron; Wu, Joseph K.; Xu, Shiyao; Zhu, Bing; Thornberry, Nancy A.; Weber, Ann E.Journal of Medicinal Chemistry (2006), 49 (12), 3614-3627CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of β-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogs led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide I, a potent, orally active DPP-4 inhibitor (IC50 = 6.3 nM) with excellent selectivity, oral bioavailability in preclin. species, and in vivo efficacy in animal models. Compd. I was selected for further characterization as a potential new treatment for type 2 diabetes.(b) Sharma, R.; Sun, H.; Piotrowski, D. W.; Ryder, T. F.; Doran, S. D.; Dai, H.; Prakash, C. Metabolism, excretion, and pharmacokinetics of (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human. Drug Metab. Dispos. 2012, 40, 2143– 2161, DOI: 10.1124/dmd.112.047316 - 52Tremblay, M.; Bethell, R. C.; Cordingley, M. G.; Deroy, P.; Duan, J.; Duplessis, M.; Edwards, P. J.; Faucher, A. M.; Halmos, T.; James, C. A.; Kuhn, C.; Lacoste, J. E.; Lamorte, L.; LaPlante, S. R.; Malenfant, É.; Minville, J.; Morency, L.; Morin, S.; Rajotte, D.; Salois, P.; Simoneau, B.; Tremblay, S.; Sturino, C. F. Identification of benzofurano-[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2775– 2780, DOI: 10.1016/j.bmcl.2013.02.042
- 53(a) Meyer, A.; Imming, P. Benzylisoquinoline alkaloids from the papaveraceae: the heritage of Johannes Gadamer (1867–1928). J. Nat. Prod. 2011, 74, 2482– 2487, DOI: 10.1021/np2005049 .(b) Sriram, D.; Yogeeswari, P.; Thirumurugan, R.; Ratan Bal, T. R. Camptothecin and its analogues: a review on their chemotherapeutic potential. Nat. Prod. Res. 2005, 19, 393– 412, DOI: 10.1080/14786410412331299005[Crossref], [PubMed], [CAS], Google Scholar.53bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvFajsrY%253D&md5=7149d979a0e7915678cce4ba5ea8aabbCamptothecin and its analogues: a review on their chemotherapeutic potentialSriram, Dharmarajan; Yogeeswari, Perumal; Thirumurugan, Rathinasabapathy; Ratan Bal, TanushreeNatural Product Research (2005), 19 (4), 393-412CODEN: NPRAAT; ISSN:1478-6419. (Taylor & Francis Ltd.)A review. Topoisomerase I (Topo-I) is a major target for anticancer drug discovery and design. As a result, Topo-I inhibitors constitute an important class of the current anticancer drugs. To date, all of the Topo-I inhibitors that have been clin. evaluated are analogs of camptothecin (CPT), an ext. of the Chinese tree Camptotheca acuminata. CPT has shown significant antitumor activity to lung, ovarian, breast, pancreas and stomach cancers. In this article the, phytochem. aspect, and various structural modifications are comprehensively reviewed as in rings A, B, C, D and E. Biol. activity of camptothecin, other than anticancer, reported till the year 2003 has also been discussed.(c) Olsen, L. R.; Grillo, M. P.; Skonberg, C. Constituents in kava extracts potentially involved in hepatotoxicity: a review. Chem. Res. Toxicol. 2011, 24, 992– 1002, DOI: 10.1021/tx100412m[ACS Full Text
], [CAS], Google Scholar53chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVKkt7k%253D&md5=5b363f611377100cf43a4f74d1595d67Constituents in Kava Extracts Potentially Involved in Hepatotoxicity: A ReviewOlsen, Line R.; Grillo, Mark P.; Skonberg, ChristianChemical Research in Toxicology (2011), 24 (7), 992-1002CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. Aq. kava root prepns. have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava exts. in Western countries, where mainly ethanolic or acetonic exts. are used. The mechanism of toxicity has not been established, although several theories have been put forward. The compn. of the major constituents, the kava lactones, varies according to prepn. method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain compn. of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chem. structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones were identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addn. of GSH to kava exts. has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava ext., such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries. - 54Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 67– 84, DOI: 10.2174/1389200003339270[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlt1Whurs%253D&md5=dcafc824c8bcd0080d256d6dd8c50ae7Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidationMurray, MichaelCurrent Drug Metabolism (2000), 1 (1), 67-84CODEN: CDMUBU ISSN:. (Bentham Science Publishers Ltd.)A review with 110 refs. Cytochrome P 450 (CYP) enzymes catalyze the oxidative conversion of drugs and other lipophilic compds. to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidn. by specific CYPs, whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compds. have been widely employed as com. important pesticide synergists and a no. of derivs. are found in oils and spices. MDP compds. are of considerable toxicol. significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivs. produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clin. importance that possess the MDP structural feature, the synthesis and preclin. evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compds. it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chem. mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clin. value of new drugs.
- 55(a) Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; O’Donnell, J. P.; Boer, J.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 2005, 6, 161– 225, DOI: 10.2174/1389200054021799[Crossref], [PubMed], [CAS], Google Scholar.55ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvF2is7k%253D&md5=b16dfc2de97c40a11218ecc3043bed66A comprehensive listing of bioactivation pathways of organic functional groupsKalgutkar, Amit S.; Gardner, Iain; Obach, R. Scott; Shaffer, Christopher L.; Callegari, Ernesto; Henne, Kirk R.; Mutlib, Abdul E.; Dalvie, Deepak K.; Lee, Jae S.; Nakai, Yasuhiro; O'Donnell, John P.; Boer, Jason; Harriman, Shawn P.Current Drug Metabolism (2005), 6 (3), 161-225CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. The occurrence of idiosyncratic adverse drug reactions during late clin. trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiol. of many drug-induced adverse reactions. Therefore, a thorough examn. of the biochem. reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochem. systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compds. based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as exptl. approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.(b) Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 2011, 24, 1345– 1410, DOI: 10.1021/tx200168d[ACS Full Text
], [CAS], Google Scholar55bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXos1Whtbo%253D&md5=632b73f755738e49eb233bc8dca1fbccStructural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United StatesStepan, Antonia F.; Walker, Daniel P.; Bauman, Jonathan; Price, David A.; Baillie, Thomas A.; Kalgutkar, Amit S.; Aleo, Michael D.Chemical Research in Toxicology (2011), 24 (9), 1345-1410CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examd. as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards assocd. with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addn., the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a mol. that contains a structural alert (RM pos. or neg.) a cause for concern. Could the mol. in its parent form exert toxicity. Can a low dose drug candidate truly mitigate metab.-dependent and -independent idiosyncratic toxicity risks. In an effort to address these questions, we have retrospectively examd. 68 drugs (recalled or assocd. with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochem. characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our anal. revealed that a significant proportion (∼78-86%) of drugs assocd. with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these mols. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochem. properties such as mol. wt., lipophilicity, etc. Approx. half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chem. architecture, and many were found to be RM-pos. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely assocd. with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addn., competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-pos. drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our anal. suggests a need for a more integrated screening paradigm for chem. hazard identification in drug discovery. Thus, in addn. to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compd.(s)) for lead compds., effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compd. liabilities. However, the prospective use of such data in compd. selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiol. mechanisms assocd. with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the assocd. "body burden" of the parent drug and its metabolites will remain an overarching goal in drug discovery. - 56Bolton, J. L.; Trush, M. A.; Penning, T. M.; Dryhurst, G.; Monks, T. J. Role of quinones in toxicology. Chem. Res. Toxicol. 2000, 13, 135– 160, DOI: 10.1021/tx9902082[ACS Full Text
], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1aitr4%253D&md5=6a3064ebe344efe5fb0d53736d8f38cfRole of Quinones in ToxicologyBolton, Judy L.; Trush, Michael A.; Penning, Trevor M.; Dryhurst, Glenn; Monks, Terrence J.Chemical Research in Toxicology (2000), 13 (3), 135-160CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review and discussion with 298 refs. Quinones represent a class of toxicol. intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active mols. which can redox cycle with their semiquinone radicals, leading to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Prodn. of ROS can cause severe oxidative stress within cells through the formation of oxidized cellular macromols., including lipids, proteins, and DNA. Formation of oxidatively damaged bases such as 8-oxodeoxyguanosine has been assocd. with aging and carcinogenesis. Furthermore, ROS can activate a no. of signaling pathways, including protein kinase C and RAS. This review explores the varied cytotoxic effects of quinones using specific examples, including quinones produced from benzene, polycyclic arom. hydrocarbons, estrogens, and catecholamines. The evidence strongly suggests that the numerous mechanisms of quinone toxicity (i.e., alkylation vs. oxidative stress) can be correlated with the known pathol. of the parent compd.(s). - 57(a) Hemeryck, A.; De Vriendt, C. A.; Belpaire, F. M. Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction. Drug Metab. Dispos. 2001, 29, 656– 663.(b) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [3H]-paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 1649– 1657, DOI: 10.1021/tx700132x .(c) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289– 293, DOI: 10.1124/dmd.31.3.289[Crossref], [PubMed], [CAS], Google Scholar57chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFKlt7Y%253D&md5=2336fbc058e49e7b530562809c62ba09Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidineBertelsen, Kirk M.; Venkatakrishnan, Karthik; Von Moltke, Lisa L.; Obach, R. Scott; Greenblatt, David J.Drug Metabolism and Disposition (2003), 31 (3), 289-293CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P 450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To det. whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estd. by varying the time of preincubation as well as the concn. of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estn. of both an apparent inactivator concn. required for half-maximal inactivation (KI) and the maximal rate const. of inactivation (KINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approx. 8-fold redn. in the IC50 value (0.34 vs. 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent KINACT value of 0.17 min-1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metab. of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P 450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.
- 58(a) Anzali, S.; Mederski, W. W. K. R.; Osswald, M.; Dorsch, D. 1. Endothelin antagonists: search for surrogates of methylendioxyphenyl by means of a kohonen neural network. Bioorg. Med. Chem. Lett. 1998, 8, 11– 16, DOI: 10.1016/S0960-894X(97)10150-0 .(b) Iyengar, R. R.; Lynch, J. K.; Mulhern, M. M.; Judd, A. S.; Freeman, J. C.; Gao, J.; Souers, A. J.; Zhao, G.; Wodka, D.; Falls, H. D.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.; Swanson, S.; Su, Z.; Martin, R. L.; Leitz, S. T.; Houseman, K. A.; Diaz, G.; Collins, C. A.; Sham, H. L.; Kym, P. R. An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2007, 17, 874– 878, DOI: 10.1016/j.bmcl.2006.11.065 .(c) Bardelle, C.; Barlaam, B.; Brooks, N.; Coleman, T.; Cross, D.; Ducray, R.; Green, I.; Lambert-van der Brempt, C.; Olivier, A.; Read, J. Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 6242– 6245, DOI: 10.1016/j.bmcl.2010.08.100 .(d) Orr, S. T. M.; Ripp, S. L.; Ballard, T. E.; Henderson, J. L.; Scott, D. O.; Obach, R. S.; Sun, H.; Kalgutkar, A. S. Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure–activity relationships and discovery strategies to mitigate drug–drug interaction risks. J. Med. Chem. 2012, 55, 4896– 4933, DOI: 10.1021/jm300065h[ACS Full Text.
], [CAS], Google Scholar58dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wlur8%253D&md5=aa4aa4f633b3b4f73b3d79917327b0deMechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure-Activity Relationships and Discovery Strategies To Mitigate Drug-Drug Interaction RisksOrr, Suvi T. M.; Ripp, Sharon L.; Ballard, T. Eric; Henderson, Jaclyn L.; Scott, Dennis O.; Obach, R. Scott; Sun, Hao; Kalgutkar, Amit S.Journal of Medicinal Chemistry (2012), 55 (11), 4896-4933CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The importance of mitigating drug-drug interaction (DDI) risks, which arise from inhibition of major human cytochrome P 450 enzymes is a well-established component of the lead optimization process in drug discovery. More recently, there has been much interest in clin. DDIs potentially arising via time- and concn.-dependent cytochrome P 450 inhibition, a phenomenon consistent with mechanism-based inactivation. Inactivated P 450 is catalytically incompetent and must be replenished by newly synthesized protein. Consequently, time-dependent inhibition of P450s presents a greater safety concern compared to reversible inhibition because of the increased propensity for pharmacokinetic interactions upon multiple dosing and the sustained duration of these interactions after discontinuation of the mechanism-based inactivator. Mechanism-based or time-dependent P 450 inhibitors pose an addnl. risk of idiosyncratic drug toxicity since the mechanism of time-dependency often involves the formation of reactive metabolites, which can react with proteins other than the P 450 isoenzyme responsible for catalysis. in vitro time-dependent inhibition (TDI) of P 450 enzymes is now routinely assessed as part of lead optimization efforts in preclin. drug discovery. However, identification of an in vitro TDI liability can raise several questions such as: What is the mechanism of TDI. Does it involve the formation of reactive metabolites. Is there a 1:1 correlation between P 450 TDI and RM formation (as measured from reactive metabolite trapping studies). What is the likelihood that a P 450 time-dependent inhibitor will also cause toxicity. What are the DDI risk mitigation options when dealing with P 450 inactivators in drug discovery - compd. progression or termination. Several drugs exhibit in vitro TDI of P 450 enzymes, but only a fraction thereof causes clin. DDIs. Hence, when do we initiate labor-intensive medicinal chem. efforts to design compds. devoid of P 450 TDI liability. What are the best methods to precisely predict the likelihood of occurrence of clin. DDIs with drug candidates that inactivate P 450 enzymes. What are (if any) the qualifying considerations for clin. progression of a P 450 time-dependent inactivator with projected clin. DDI risks. In an effort to address these questions and hopefully provide answers to some of them, we embarked on the present venture wherein we highlight the current state-of-the-art knowledge in this field with a special emphasis on (a) available biochem. and mechanistic approaches in drug discovery to examine TDI of P 450 isoenzymes with new chem. entities, (b) structure-activity relationship studies with marketed drugs assocd. with DDIs via P 450 inactivation, (c) case studies of medicinal chem. tactics to abrogate P 450 inactivation liability, (d) strategies for progression of P 450 TDI-pos. drug candidates, and (e) the utility of in silico methodol., including the use of physiol.-based pharmacokinetic simulators, in drug discovery to predict the magnitude of clin. DDIs risks anticipated with new clin. candidates.(e) Crawford, J. J.; Kenny, P. W.; Bowyer, J.; Cook, C. R.; Finlayson, J. E.; Heyes, C.; Highton, A. J.; Hudson, J. A.; Jestel, A.; Krapp, S.; Martin, S.; MacFaul, P. A.; McDermott, B. P.; McGuire, T. M.; Morley, A. D.; Morris, J. J.; Page, K. M.; Rosenbrier Ribeiro, L.; Sawney, H.; Steinbacher, S.; Smith, C.; Dossetter, A. G. Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors. J. Med. Chem. 2012, 55, 8827– 8837, DOI: 10.1021/jm301119s - 59Uttamsingh, V.; Gallegos, R.; Liu, J. F.; Harbeson, S. L.; Bridson, G. W.; Cheng, C.; Wells, D. S.; Graham, P. B.; Zelle, R.; Tung, R. Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine. J. Pharmacol. Exp. Ther. 2015, 354, 43– 54, DOI: 10.1124/jpet.115.223768[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFalsLrN&md5=8e7fa68ba7ab319df75badeb50700c20Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetineUttamsingh, Vinita; Gallegos, Richard; Liu, Julie F.; Harbeson, Scott L.; Bridson, Gary W.; Cheng, Changfu; Wells, David S.; Graham, Philip B.; Zelle, Robert; Tung, RogerJournal of Pharmacology and Experimental Therapeutics (2015), 354 (1), 43-54CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Selective deuterium substitution as a means of ameliorating clin. relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium. The new chem. entity, CTP-347 [(3S,4R)-3-((2,2-dideuterobenzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine], demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, as unmodified paroxetine. However, human liver microsomes cleared CTP-347 faster than paroxetine as a result of decreased inactivation of CYP2D6. In phase 1 studies, CTP-347 wasmetabolized more rapidly in humans and exhibited a lower pharmacokinetic accumulation index than paroxetine. These alterations in the metab. profile resulted in significantly reduced drug-drug interactions between CTP-347 and two other CYP2D6-metabolized drugs: tamoxifen (in vitro) and dextromethorphan (in humans). Our results show that precision deuteration can improve the metab. profiles of existing pharmacotherapies without affecting their intrinsic pharmacologies.
- 60(a) Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers, A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh, K. C.; Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2. Bioorg. Med. Chem. Lett. 2004, 14, 4879– 4882, DOI: 10.1016/j.bmcl.2004.07.034 .(b) Nuzzi, A.; Fiasella, A.; Ortega, J. A.; Pagliuca, C.; Ponzano, S.; Pizzirani, D.; Mandrup Bertozzi, S.; Ottonello, G.; Tarozzo, G.; Reggiani, A.; Bandiera, T.; Bertozzi, F.; Piomelli, D. Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies. Eur. J. Med. Chem. 2016, 111, 138– 159, DOI: 10.1016/j.ejmech.2016.01.046[Crossref], [PubMed], [CAS], Google Scholar60bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisVansL4%253D&md5=639c2848d70ba68008db89244c2c8657Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studiesNuzzi, Andrea; Fiasella, Annalisa; Ortega, Jose Antonio; Pagliuca, Chiara; Ponzano, Stefano; Pizzirani, Daniela; Bertozzi, Sine Mandrup; Ottonello, Giuliana; Tarozzo, Glauco; Reggiani, Angelo; Bandiera, Tiziano; Bertozzi, Fabio; Piomelli, DanieleEuropean Journal of Medicinal Chemistry (2016), 111 (), 138-159CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate I is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, the authors describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivs., which have led to the identification of I, and expand these studies to elucidate the principal structural and stereochem. features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of II, a novel inhibitor of human NAAA that shows an improved physicochem. and drug-like profile relative to I. This favorable profile, along with the structural diversity of the carbamic acid chain of I, identify this compd. as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.
- 61(a) Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci, F. C.; Gao, Y.; Moorjani, M.; Connors, P. .J., Jr.; Rowbottom, M. W.; Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders, J.; Reinhart, G.; Chen, T. K.; Killam Bonneville, A. L.; Chen, C. Synthesis and Structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists. J. Med. Chem. 2004, 47, 1259– 1271, DOI: 10.1021/jm030472z .(b) Lynch, J. K.; Freeman, J. C.; Judd, A. S.; Iyengar, R.; Mulhern, M.; Zhao, G.; Napier, J. J.; Wodka, D.; Brodjian, S.; Dayton, B. D.; Falls, D.; Ogiela, C.; Reilly, R. M.; Campbell, T. J.; Polakowski, J. S.; Hernandez, L.; Marsh, K. C.; Shapiro, R.; Knourek-Segel, V.; Droz, B.; Bush, E.; Brune, M.; Preusser, L. C.; Fryer, R. M.; Reinhart, G. A.; Houseman, K.; Diaz, G.; Mikhail, A.; Limberis, J. T.; Sham, H. L.; Collins, C. A.; Kym, P. R. Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety. J. Med. Chem. 2006, 49, 6569– 6584, DOI: 10.1021/jm060683e
- 62Malamas, M. S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A. J. Aminoimidazoles as potent and selective human β-secretase (BACE1) inhibitors. J. Med. Chem. 2009, 52, 6314– 6323, DOI: 10.1021/jm9006752
- 63Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 73– 85, DOI: 10.1007/s00280-005-0128-y[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslGjsbg%253D&md5=97ecbd7d19b5e051255c5c0dc03b215aNovel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterizationRose, William C.; Marathe, Punit H.; Jang, Graham R.; Monticello, Thomas M.; Balasubramanian, Balu N.; Long, Byron; Fairchild, Craig R.; Wall, Monroe E.; Wani, Mansukh C.Cancer Chemotherapy and Pharmacology (2006), 58 (1), 73-85CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacol., toxicol., metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compds. for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclin. antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicol. assessment of GI injury in mice. The generation of parent compd. from BMS-422461 was qual. similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equil. was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclin. GI toxicity, make this novel camptothecin analog attractive for clin. development.
- 64Trachsel, D.; Hadorn, M.; Baumberger, F. Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives. Chem. Biodivers. 2009, 6, 2115– 2135
- 65(a) Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.; Burton, B.; Stack, J. H.; Straley, K. S.; Decker, C. J.; Miller, M.; McCartney, J.; Olson, E. R.; Wine, J. J.; Frizzell, R. A.; Ashlock, M.; Negulescu, P. A. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 18843– 18848, DOI: 10.1073/pnas.1105787108[Crossref], [PubMed], [CAS], Google Scholar.65ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1WnsL%252FO&md5=26ad0866327fd2f645bcc68e91c87354Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (46), 18843-18848, S18843/1-S18843/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amts. of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small mols. Here we describe the in vitro pharmacol. of VX-809, a CFTR corrector that was advanced into clin. development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approx. 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level assocd. with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR cor. by VX-809 exhibited biochem. and functional characteristics similar to normal CFTR, including biochem. susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.(b) Deeks, E. D. Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs 2016, 76, 1191– 1201, DOI: 10.1007/s40265-016-0611-2[Crossref], [PubMed], [CAS], Google Scholar65bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFOmu7bO&md5=7be2b21495bde10b6ed5eb826e53613fLumacaftor/Ivacaftor: A Review in Cystic FibrosisDeeks, Emma D.Drugs (2016), 76 (12), 1191-1201CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Lumacaftor/ivacaftor (Orkambi) is a fixed-dose tablet contg. a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-wk trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with std. therapy, was assocd. with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory vol. in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clin. meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clin. benefit over a further 72 wk of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clin. practice remains to be detd.
- 66Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 1204– 1208, DOI: 10.1021/acsmedchemlett.5b00353[ACS Full Text
], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGms73P&md5=fc681414ace29f39906fdd62c204114bPreclinical Characterization of the FAAH Inhibitor JNJ-42165279Keith, John M.; Jones, William M.; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A.; Webb, Michael; Karbarz, Mark; Scott, Brian P.; Wilson, Sandy J.; Luo, Lin; Wennerholm, Michelle L.; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R.; Breitenbucher, J. GuyACS Medicinal Chemistry Letters (2015), 6 (12), 1204-1208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The preclin. characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 I is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concns. of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compd. was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good phys., ADME, and PD properties of JNJ-42165279 supported it entering the clin. portfolio. - 67Buissonneaud, D. Y.; van Mourik, T.; O’Hagan, D. A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes. Tetrahedron 2010, 66, 2196– 2202, DOI: 10.1016/j.tet.2010.01.049[Crossref], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXitleiurk%253D&md5=b7d6e3599c8e0b9a6364f55c34f362afA DFT study on the origin of the fluorine gauche effect in substituted fluoroethanesBuissonneaud, David Y.; van Mourik, Tanja; O'Hagan, DavidTetrahedron (2010), 66 (12), 2196-2202CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)DFT derived conformational energy profiles of a series of β-substituted α-fluoroethanes (F-CH2CH2-X) have been explored where the substituent X was varied as NH3+, OCOH, NCO, NO2, NHCHO, F, N3, CH=NH, NCS, CH=C=CH2, CH3, CH=CH2, NC, CN, CHO, and CCH. Comparisons were correlated relative to 1,2-difluoroethane, a compd. which exhibits a well known gauche preference. Only four of the compds. displayed an anti preference, with the large majority preferring a gauche conformation. In particular the influence of steric and electrostatic attraction/repulsion between the fluorine atom and the X-substituent was explored by evaluating rotational energy profiles for all compds. and sep. NBO correlations were evaluated to assess the contribution of hyperconjugation to the minimized gauche and anti conformers. In the event the gauche preference for 1,2-difluoroethane was shown to have an origin due largely to σ(C-H)→σ*(C-F) hyperconjugative interactions, whereas the conformational preference for the remaining structures is rationalized by hyperconjugative as well as steric and electrostatic contributions. The anti preferred compds. 13, 14 and 16 possessed triple bonds and the preference arose due to fluorine/p-orbital repulsion.
- 68(a) Deniau, G.; Slawin, A. M. Z.; Lebl, T.; Chorki, F.; Issberner, J. P.; van Mourik, T.; Heygate, J. M.; Lambert, J. J.; Etherington, L. A.; Sillar, K. T.; O’Hagan, D. Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analogue of the neurotransmitter GABA. ChemBioChem 2007, 8, 2265– 2274, DOI: 10.1002/cbic.200700371[Crossref], [PubMed], [CAS], Google Scholar.68ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltlentbc%253D&md5=9ebd7a5dc80ad3dd9c711572f1304f32Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analog of the neurotransmitter GABADeniau, Gildas; Slawin, Alexandra M. Z.; Lebl, Tomas; Chorki, Fatima; Issberner, Jon P.; van Mourik, Tanja; Heygate, Judith M.; Lambert, Jeremy J.; Etherington, Lori-An; Sillar, Keith T.; O'Hagan, DavidChemBioChem (2007), 8 (18), 2265-2274CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)β-Aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calcns. were carried out in a continuum solvent model (PCM-B3LYP) to est. the preferred conformations of 3F-GABA in aq. soln. NMR coupling consts. were calcd. for each conformer and were then used to simulate the NMR spectra to evaluate the soln. conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABAA receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).(b) Yamamoto, I.; Deniau, G. P.; Gavande, N.; Chebib, M.; Johnston, G. A. R.; O’Hagan, D. Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABAC receptors. Chem. Commun. 2011, 47, 7956– 7958, DOI: 10.1039/c1cc12141c .(c) Clift, M. D.; Ji, H.; Deniau, G. P.; O’Hagan, D.; Silverman, R. B. Enantiomers of 4-amino-3-fluorobutanoic acid as substrates for γ-aminobutyric acid aminotransferase. Conformational probes for GABA binding. Biochemistry 2007, 46, 13819– 13828, DOI: 10.1021/bi701249q[ACS Full Text.
], [CAS], Google Scholar68chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1OhsbrO&md5=40d7bf78aab98245d752399c4f468bf1Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA BindingClift, Michael D.; Ji, Haitao; Deniau, Gildas P.; O'Hagan, David; Silverman, Richard B.Biochemistry (2007), 46 (48), 13819-13828CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)γ-Aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degrdn. of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of α-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)- and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH3+ bonds have a strong preference to align gauche rather than anti to each other, it is concluded that on binding of free 3-F-GABA to GABA-AT the optimal conformation places the C-NH3+ and C-F bonds gauche in the (R)-enantiomer but anti in the (S)-enantiomer. Furthermore, the dynamic binding process and the bioactive conformation of GABA bound to GABA-AT have been inferred on the basis of the different biol. behavior of the two enantiomers of 3-F-GABA when they bind to the enzyme. The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily detd. by other biophys. approaches.(d) Crittenden, D. L.; Chebib, M.; Jordan, M. J. T. A quantitative structure-activity relationship investigation into agonist binding at GABAC receptors. J. Mol. Struct.: THEOCHEM 2005, 755, 81– 89, DOI: 10.1016/j.theochem.2005.07.029[Crossref], [CAS], Google Scholar68dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yjt7nI&md5=7993d476114d34309580bfb8ebd06b1dA quantitative structure-activity relationship investigation into agonist binding at GABAC receptorsCrittenden, Deborah L.; Chebib, Mary; Jordan, Meredith J. T.Journal of Molecular Structure: THEOCHEM (2005), 755 (1-3), 81-89CODEN: THEODJ; ISSN:0166-1280. (Elsevier B.V.)The quant. structure-activity relationship (QSAR) model constructed in this work represents the first quant. investigation into agonist binding at GABAC receptors. This model is based upon the three-dimensional structures of γ-aminobutyric acid (GABA) and 12 other biol. active GABA analogs. These structures are obtained by geometry optimization and conformational exploration at MP2/6-31 + G* within the conductor-like screening solvation model (COSMO). The biol. activity data are obtained from previous two-electrode voltage clamp electrophysiol. studies on recombinant GABAC ρ1 receptors expressed in Xenopus laevis oocytes. A QSAR model to predict GABAC agonist binding is constructed from mol. superposition data, generated by least-squares superposition of the stable aq. phase conformations of GABA and its known biol. active analogs to the bioactive conformation of TACA, the most potent GABAC receptor agonist. A significant relationship is found between the root-mean-squared deviation in at. position for the stable conformer of each GABA analog most closely fitting the template TACA structure and the natural log of the normalized biol. activity (R2 = 0.91, p < 0.0001), On the basis of mol. superposition and QSAR results, a pharmacophore model describing three-dimensional features and key interactions at the GABAC receptor binding site is proposed. As there exists no direct exptl. knowledge of structure of the GABAC binding site, this approach provides a feasible and reliable alternative to gain insight into its three-dimensional structure. - 69(a) Hunter, L.; Jolliffe, K. A.; Jordan, M. J. T.; Jensen, P.; MacQuart, R. B. Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivatives. Chem. - Eur. J. 2011, 17, 2340– 2343, DOI: 10.1002/chem.201003320[Crossref], [PubMed], [CAS], Google Scholar.69ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvVWrurw%253D&md5=267a708d47f0c1d6d0eaf4a7278693b0Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivativesHunter, Luke; Jolliffe, Katrina A.; Jordan, Meredith J. T.; Jensen, Paul; MacQuart, Rene B.Chemistry - A European Journal (2011), 17 (8), 2340-2343, S2340/1-S2340/61CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Synthetic access has been archived to all possible stereoisomers of the α,β-difluoro-γ-amino acid motif. These building blocks can readily be coupled to other amino acids under std. conditions with no detectable epimerization, and the resulting, diastereomeric peptides exhibit different, but predictable, conformational behavior. The α,β-difluoro-γ-amino acid motif described here should be of relevance in the future design of shape-controlled bioactive amino acids and peptides.(b) Yamamoto, I.; Jordan, M. J. T.; Gavande, N.; Doddareddy, M. R.; Chebib, M.; Hunter, L. The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABA C receptor. Chem. Commun. 2012, 48, 829– 831, DOI: 10.1039/C1CC15816C[Crossref], [PubMed], [CAS], Google Scholar69bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ersbnK&md5=f48028676c58c2cfafeef583055a10d6The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABAC receptorYamamoto, Izumi; Jordan, Meredith J. T.; Gavande, Navnath; Doddareddy, Munikumar R.; Chebib, Mary; Hunter, LukeChemical Communications (Cambridge, United Kingdom) (2012), 48 (6), 829-831CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)The conformational behavior and GABA receptor activity of the different stereoisomers of 2,3-difluoro-4-aminobutyric acid are described. Two enantiomeric GABAC-active ligands are identified, one of which is an agonist while the other is an antagonist. The results support an existing QSAR model of the bioactive geometry of GABA at GABAC.
- 70Chia, P. W.; Livesey, M. R.; Slawin, A. M. Z.; Van Mourik, T.; Wyllie, D. J. A.; O’Hagan, D. 3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) stereoisomers as conformational probes for exploring agonist binding at NMDA receptors. Chem. - Eur. J. 2012, 18, 8813– 8819, DOI: 10.1002/chem.201200071[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1amu7k%253D&md5=7cba940c2e8ac7341e18ebd9131d7cb33-Fluoro-N-methyl-L-aspartic acid (3F-NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA ReceptorsChia, Poh Wai; Livesey, Matthew R.; Slawin, Alexandra M. Z.; Mourik, Tanja van; Wyllie, David J. A.; O'Hagan, DavidChemistry - A European Journal (2012), 18 (28), 8813-8819, S8813/1-S8813/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)N-Methyl-L-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C-F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepd. by synthesis in enantiomerically pure forms and (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C-F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C-N+ bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilization, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the mol. conformation of β-fluorinated amino acids and thus probing the active conformations of bioactive compds. at receptors.
- 71Hu, X. G.; Thomas, D. S.; Griffith, R.; Hunter, L. Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A. Angew. Chem., Int. Ed. 2014, 53, 6176– 6179, DOI: 10.1002/anie.201403071[Crossref], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosV2hurg%253D&md5=38d2e98bd5d45c24d9f020857cc87b90Stereoselective fluorination alters the geometry of a cyclic peptide: Exploration of backbone-fluorinated analogues of Unguisin AHu, Xiang-Guo; Thomas, Donald S.; Griffith, Renate; Hunter, LukeAngewandte Chemie, International Edition (2014), 53 (24), 6176-6179CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)New methods for enhancing the efficiency of peptide cyclization, and for fine-tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogs of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogs are found to adopt dramatically different secondary structures, controlled by the fluorine stereochem.
- 72Hodges, J. A.; Raines, R. T. Stereoelectronic effects on collagen stability: the dichotomy of 4-fluoroproline diastereomers. J. Am. Chem. Soc. 2003, 125, 9262– 9263, DOI: 10.1021/ja035881z[ACS Full Text
], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltlCksbo%253D&md5=faf38ab73d864733c8501cd4218f74bdStereoelectronic Effects on Collagen Stability: The Dichotomy of 4-Fluoroproline DiastereomersHodges, Jonathan A.; Raines, Ronald T.Journal of the American Chemical Society (2003), 125 (31), 9262-9263CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Collagen is the most abundant protein in animals. Natural collagen consists of a triple helix of (Xaa-Yaa-Gly)n chains, in which the Xaa and Yaa residues are often L-proline. Here, a (2S,4S)-4-fluoroproline (flp) residue is shown to be greatly stabilizing in the Xaa position (but destabilizing in the Yaa position). In contrast, a (2S,4R)-4-fluoroproline (Flp) residue is shown to be greatly destabilizing in the Xaa position (but stabilizing in the Yaa position). The dichotomous effect of the diastereomers appears to arise from a gauche effect, which alters pyrrolidine ring pucker and hence properly (or improperly) preorganizes main-chain dihedral angles. Thus, the rational use of stereoelectronic effects can enhance the conformational stability of a protein. - 73(a) Jakobsche, C. E.; Choudhary, A.; Miller, S. J.; Raines, R. T. n→π* Interaction and n)(π Pauli repulsion are antagonistic for protein stability. J. Am. Chem. Soc. 2010, 132, 6651– 6653, DOI: 10.1021/ja100931y[ACS Full Text.
], [CAS], Google Scholar73ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFyrsbo%253D&md5=a85d11979744c915d9c0c37756d76225n → π* Interaction and n)(π Pauli Repulsion Are Antagonistic for Protein StabilityJakobsche, Charles E.; Choudhary, Amit; Miller, Scott J.; Raines, Ronald T.Journal of the American Chemical Society (2010), 132 (19), 6651-6653CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)In many common protein secondary structures, such as α-, 310, and polyproline II helixes, an n → π* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (Oi-1) of a peptide bond over the antibonding orbital (π*) of Ci:Oi of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of Oi-1 and the bonding orbital (π) of Ci:Oi. We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n → π* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n → π* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n → π* interaction and emphasizes the quantum-mech. nature of the interaction between adjacent amide carbonyl groups in proteins.(b) Newberry, R. W.; VanVeller, B.; Guzei, I. A.; Raines, R. T. n→π* Interactions of amides and thioamides: implications for protein stability. J. Am. Chem. Soc. 2013, 135, 7843– 7846, DOI: 10.1021/ja4033583[ACS Full Text.
], [CAS], Google Scholar73bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsFarsLY%253D&md5=0650f8f39cc5a3eb4a7d3ec6ae760eb4n→π* Interactions of Amides and Thioamides: Implications for Protein StabilityNewberry, Robert W.; VanVeller, Brett; Guzei, Ilia A.; Raines, Ronald T.Journal of the American Chemical Society (2013), 135 (21), 7843-7846CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Carbonyl-carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining exptl. and computational approaches, we show that relevant amidic carbonyl groups assoc. through an n→π* donor-acceptor interaction with an energy of at least 0.27 kcal/mol. The n→π* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor-acceptor orbital interactions rather than dipole-dipole interactions.(c) Kamer, K. J.; Choudhary, A.; Raines, R. T. Intimate interactions with carbonyl groups: dipole-dipole or n→π*?. J. Org. Chem. 2013, 78, 2099– 2103, DOI: 10.1021/jo302265k[ACS Full Text
], [CAS], Google Scholar73chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12mt7jN&md5=a5d3bdd610f31a274d68099bcdf39210Intimate Interactions with Carbonyl Groups: Dipole-Dipole or n→π*?Kamer, Kimberli J.; Choudhary, Amit; Raines, Ronald T.Journal of Organic Chemistry (2013), 78 (5), 2099-2103CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Amide carbonyl groups in proteins can engage in C-O···C=O and C-X···C=O interactions, where X is a halogen. The putative involvement of four poles suggests that these interactions are primarily dipolar. Our survey of crystal structures with a C-X···C=O contact that is short (i.e., within the sum of the X and C van der Waals radii) revealed no preferred C-X···C=O dihedral angle. Moreover, we found that structures with a short X-···C=O contact display the signatures of an n→π* interaction. We conclude that intimate interactions with carbonyl groups do not require a dipole. - 74Fukushima, H.; Hiratate, A.; Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y.; Yamamoto, K. Synthesis and structure–activity relationships of potent 3- or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. 2004, 12, 6053– 6061, DOI: 10.1016/j.bmc.2004.09.010
- 75Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J. D.; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A.-M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Extended structure–activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J. Med. Chem. 2014, 57, 3053– 3074, DOI: 10.1021/jm500031w[ACS Full Text
], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXktVSjt7Y%253D&md5=c52e7b0f1b7a7b056a74577c262a1d6dExtended Structure-Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)Jansen, Koen; Heirbaut, Leen; Verkerk, Robert; Cheng, Jonathan D.; Joossens, Jurgen; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van der Veken, PieterJournal of Medicinal Chemistry (2014), 57 (7), 3053-3074CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncol. applications. The authors previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, the authors explore in detail the structure-activity relationship around this core scaffold. The authors report extensively optimized compds. that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compds. were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo. - 76Staas, D. D.; Savage, K. L.; Sherman, V. L.; Shimp, H. L.; Lyle, T. A.; Tran, L. O.; Wiscount, C. M.; McMasters, D. R.; Sanderson, P. E. J.; Williams, P. D.; Lucas, B. J., Jr.; Krueger, J. A.; Lewis, S. D.; White, R. B.; Yu, S.; Wong, B. K.; Kochansky, C. J.; Anari, M. R.; Yan, Y.; Vacca, J. P. Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability. Bioorg. Med. Chem. 2006, 14, 6900– 6916, DOI: 10.1016/j.bmc.2006.06.040[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptFSksL8%253D&md5=f59e8094ff012efcea5b4ca0a053f4feDiscovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stabilityStaas, Donnette D.; Savage, Kelly L.; Sherman, Vanessa L.; Shimp, Heidi L.; Lyle, Terry A.; Tran, Lekhanh O.; Wiscount, Catherine M.; McMasters, Daniel R.; Sanderson, Philip E. J.; Williams, Peter D.; Lucas, Bobby J.; Krueger, Julie A.; Lewis, S. Dale; White, Rebecca B.; Yu, Sean; Wong, Bradley K.; Kochansky, Christopher J.; Anari, M. Reza; Yan, Youwei; Vacca, Joseph P.Bioorganic & Medicinal Chemistry (2006), 14 (20), 6900-6916CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Previous reports from our labs. described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compds. for further optimization, we identified sites of metab. and designed analogs with 4-fluoroproline in P2 and cyclopropane-contg. side chains in P3 as an approach to reducing metab. and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs contg. (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compds. and by mol. modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compd. from this work, 41 (I), exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity vs. the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
- 77Chiba, J.; Takayama, G.; Takashi, T.; Yokoyama, M.; Nakayama, A.; Baldwin, J. J.; McDonald, E.; Moriarty, K. J.; Sarko, C. R.; Saionz, K. W.; Swanson, R.; Hussain, Z.; Wong, A.; MachinagA, N. Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists. Bioorg. Med. Chem. 2006, 14, 2725– 2746, DOI: 10.1016/j.bmc.2005.11.058
- 78(a) Wang, Y.; Callejo, R.; Slawin, A. M. Z.; O’Hagan, D. The difluoromethylene (CF2) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groups. Beilstein J. Org. Chem. 2014, 10, 18– 25, DOI: 10.3762/bjoc.10.4[Crossref], [PubMed], [CAS], Google Scholar.78ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtFajsLY%253D&md5=08f75f8b382be17a4a74f268267083d5The difluoromethylene (CF2) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groupsWang, Yi; Callejo, Ricardo; Slawin, Alexandra M. Z.; O'Hagan, DavidBeilstein Journal of Organic Chemistry (2014), 10 (), 18-25, 8 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)The syntheses of palmitic acids and a nonadecane are reported with CF2 groups located 1,3 or 1,4 to each other along the aliph. chain. Specifically 8,8,10,10- and 8,8,11,11-tetrafluorohexadecanoic acids are prepd. as well as the singly modified analog 8,8-difluorohexadecanoic acid. Also 8,8,11,11-tetrafluorononadecane is prepd. as a pure hydrocarbon contg. a 1,4-di-CF2 motif. The modified palmitic acids are characterized by differential scanning calorimetry (DSC) to det. m.ps. and phase behavior relative to palmitic acid (62.5 °C). It emerges that 8,8,11,11-tetrafluorohexadecanoic acid, with the CF2 groups placed 1,4- to each other, has a significantly higher m.p. (89.9 °C) when compared to the other analogs and palmitic acid itself. It is a cryst. compd. and the structure reveals an extended anti-zig-zag chain. Similarly 8,8,11,11-tetrafluorononadecane adopts an extended anti-zig-zag structure. This is rationalized by dipolar relaxation between the two CF2 groups placed 1,4 to each other in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce conformational stability.(b) Tavasli, M.; O’Hagan, D.; Pearson, C.; Petty, M. C. The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acids. Chem. Commun. 2002, 1226– 1227, DOI: 10.1039/b202891c[Crossref], [PubMed], [CAS], Google Scholar78bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjslaltL0%253D&md5=19df1ebbe3a055d98534780d93b3e2d9The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acidsTavasli, Mustafa; O'Hagan, David; Pearson, Christopher; Petty, Michael C.Chemical Communications (Cambridge, United Kingdom) (2002), (11), 1226-1227CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)(±)-Erythro- and (±)-threo- 9,10-difluorostearic acids, which differ only by a stereogenic interconversion of a single C-F bond, have significantly different conformational stabilities.
- 79(a) O’Hagan, D. Organofluorine chemistry: synthesis and conformation of vicinal fluoromethylene motifs. J. Org. Chem. 2012, 77, 3689– 3699, DOI: 10.1021/jo300044q[ACS Full Text.
], [CAS], Google Scholar79ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wltbg%253D&md5=fdc040b0921c21fe3c539031e2f6c624Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene MotifsO'Hagan, DavidJournal of Organic Chemistry (2012), 77 (8), 3689-3699CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A review. The C-F bond is the most polar bond in org. chem., and thus the bond has a relatively large dipole moment with a significant -ve charge d. on the fluorine atom and correspondingly a +ve charge d. on carbon. The electrostatic nature of the bond renders it the strongest one in org. chem. However, the fluorine atom itself is nonpolarizable, and thus, despite the charge localization on fluorine, it is a poor hydrogen-bonding acceptor. These properties of the C-F bond make it attractive in the design of nonviscous but polar org. compds., with a polarity limited to influencing the intramol. nature of the mol. and less so intermol. interactions with the immediate environment. In this perspective, the synthesis of aliph. chains carrying multivicinal fluoromethylene motifs is described. It emerges that the dipoles of adjacent C-F bonds orientate relative to each other, and thus, individual diastereoisomers display different backbone carbon chain conformations. These conformational preferences recognize the influence of the well-known gauche effect assocd. with 1,2-difluoroethane but extend to considering 1,3-fluorine-fluorine dipolar repulsions. The synthesis of carbon chains carrying two, three, four, five, and six vicinal fluoromethylene motifs is described, with an emphasis on the research done by the authors. These motifs obey almost predictable conformational behavior, and they emerge as candidates for inclusion in the design of performance org. mols.(b) Wu, D.; Tian, A.; Sun, H. Conformational properties of 1,3-difluoropropane. J. Phys. Chem. A 1998, 102, 9901– 9905, DOI: 10.1021/jp982164w[ACS Full Text.
], [CAS], Google Scholar79bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFKnt7Y%253D&md5=f44c4fc0316ebf223dc223162a793c04Conformational properties of 1,3-difluoropropaneWu, D.; Tian, A.; Sun, H.Journal of Physical Chemistry A (1998), 102 (48), 9901-9905CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The conformational energy order of F(CH2)3F (I) is identified as GG < AG < AA < GG' at various ab initio calcn. levels. This result is analyzed on the basis of the mol. structures, partial charge distributions, and a mol.-mechanics calcn. A strong dipole-dipole interaction between the highly polarized C-F bonds is the decisive factor detg. the conformational-energy preference between 2 gauche-gauche conformers (GG and GG'). This observation suggests that, in addn. to the gauche effect, the intramol. electrostatic interaction should be considered for studying conformational behaviors of mols. with highly polarized bonds in general. The conformational energies obtained in this work challenge earlier interpretations of exptl. data for I.(c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. Angew. Chem., Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.200901956[Crossref], [CAS], Google Scholar79chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFSqtb0%253D&md5=76c049e74a5ebf68bbc4800eb2a82afcSynthesis and Structure of Stereoisomeric Multivicinal HexafluoroalkanesHunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, DavidAngewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored. - 80Scheidt, F.; Selter, P.; Santschi, N.; Holland, M. C.; Dudenko, D. V.; Daniliuc, C.; Mück-Lichtenfeld, C.; Hansen, M. R.; Gilmour, R. Emulating natural product conformation by cooperative, non-covalent fluorine interactions. Chem. - Eur. J. 2017, 23, 6142– 6149, DOI: 10.1002/chem.201604632[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFGqsLfF&md5=2add1cdf79a83f23744d3aef82b8e7ecEmulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine InteractionsScheidt, Felix; Selter, Philipp; Santschi, Nico; Holland, Mareike C.; Dudenko, Dmytro V.; Daniliuc, Constantin; Mueck-Lichtenfeld, Christian; Hansen, Michael Ryan; Gilmour, RyanChemistry - A European Journal (2017), 23 (25), 6142-6149CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Pervasive in Nature, the propane unit is an essential component of numerous bioactive mols. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclization via cyclic ether formation ensures a highly pre-organized structure, while linear scaffolds display more dynamic conformational behavior resulting from rotation about the two internal C(sp3)-C(sp3) bonds. In this study, the replacement of -[CH2]- units by -[CHF]- centers is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviors: These are encoded by the relative configuration of each center. By exploiting cooperative neighboring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theor., crystallog. and spectroscopic analyses. In view of the favorable physicochem. properties assocd. with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.
- 81Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455[ACS Full Text
], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsrzM&md5=20d7a36b75501c02570744857c82f325Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug DiscoveryHuchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, KlausJournal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences. - 82Yokokawa, F.; Wang, G.; Chan, W. L.; Ang, S. H.; Wong, J.; Ma, I.; Rao, S. P. S.; Manjunatha, U.; Lakshminarayana, S. B.; Herve, M.; Kounde, C.; Tan, B. H.; Thayalan, P.; Ng, S. H.; Nanjundappa, M.; Ravindran, S.; Gee, P.; Tan, M.; Wei, L.; Goh, A.; Chen, P.-Y.; Lee, K. S.; Zhong, C.; Wagner, T.; Dix, I.; Chatterjee, A. K.; Pethe, K.; Kuhen, K.; Glynne, R.; Smith, P.; Bifani, P.; Jiricek, J. Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. ACS Med. Chem. Lett. 2013, 4, 451– 455, DOI: 10.1021/ml400071a[ACS Full Text
], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVCltb0%253D&md5=d4a33e9a3fc688dacdb3aa2e8c1c7465Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular AgentsYokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Dick, Thomas; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, JanACS Medicinal Chemistry Letters (2013), 4 (5), 451-455CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Nonracemic (aryl)(fluoroalkyl)tetrahydropyrazolo[1,5-a]pyrimidinecarboxamides I [R = 4-MeC6H4, 5-Me-2-pyridinyl, 5-methyl-2-furyl, 4-(4-morpholinyl)C6H4, 4-(MeOCH2CH2O)C6H4, 4-(3-oxetanyloxy)C6H4; R1 = F3C, F2HC; R2 = 4-FC6H4CH2, 6-MeO-3-pyridinylmethyl, 5-F-2-pyridinylmethyl] were prepd. stereoselectively as potential antitubercular agents; their inhibition of Mycobacterium tuberculosis (Mtb), their aq. solubilities, their plasma protein binding, and their lipophilicities were detd. I were prepd. from aryl Me ketones, Et trifluoro- or difluoroacetate, and Et 3-amino-4-pyrazolecarboxylate; resoln. of the intermediate cis-aryl(fluoroalkyl)tetrahydropyrazolopyrimidinecarboxylic acids by supercrit. fluid chromatog. followed by amidation or aryl modifications yielded the desired products. While I inhibited Mtb with MIC of 0.13-52.2 μM, ent-I did not inhibit Mtb (MIC > 20 μM). In particular, I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) showed a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse antitubercular efficacy model, achieving a redn. of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB. The structure of a nonracemic (methylpyridinyl)(trifluoromethyl)tetrahydropyrazolopyrimidinecarboxylic acid intermediate and its abs. configuration were detd. by X-ray crystallog. - 83Koerts, J.; Soffers, A. E. M. F.; Vervoort, J.; De Jager, A.; Rietjens, I. M. C. M. Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes. Chem. Res. Toxicol. 1998, 11, 503– 512, DOI: 10.1021/tx980053i[ACS Full Text
], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1Giurc%253D&md5=64178da1e0f25584e5aa883b57d3498cOccurrence of the NIH Shift upon the Cytochrome P450-Catalyzed in Vivo and in Vitro Aromatic Ring Hydroxylation of FluorobenzenesKoerts, Janneke; Soffers, Ans E. M. F.; Vervoort, Jacques; De Jager, Adrie; Rietjens, Ivonne M. C. M.Chemical Research in Toxicology (1998), 11 (5), 503-512CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The in vivo cytochrome P 450-catalyzed arom. hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metab. of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro expts. showed a significant amt. of NIH-shifted metabolites for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of addnl. expts. presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metab. of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated benzenes. - 84(a) Shih, I.-h.; Vliegen, I.; Peng, B.; Yang, H.; Hebner, C.; Paeshuyse, J.; Purstinger, G.; Fenaux, M.; Tian, Y.; Mabery, E.; Qi, X.; Bahador, G.; Paulson, M.; Lehman, L. S.; Bondy, S.; Tse, W.; Reiser, H.; Lee, W. A.; Schmitz, U.; Neyts, J.; Zhong, W. Mechanistic characterization of GS-9190 (tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase. Antimicrob. Agents Chemother. 2011, 55, 4196– 4203, DOI: 10.1128/AAC.00307-11 .(b) Hebner, C. M.; Han, B.; Brendza, K. M.; Nash, M.; Sulfab, M.; Tian, Y.; Hung, M.; Fung, W.; Vivian, R. W.; Trenkle, J.; Taylor, J.; Bjornson, K.; Bondy, S.; Liu, X.; Link, J.; Neyts, J.; Sakowicz, R.; Zhong, W.; Tang, H.; Schmitz, U. The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. PLoS One 2012, 7, e39163, DOI: 10.1371/journal.pone.0039163[Crossref], [PubMed], [CAS], Google Scholar.84bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovF2jtro%253D&md5=55998f37569ff6b657425bf95a0b677dThe HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase functionHebner, Christy M.; Han, Bin; Brendza, Katherine M.; Nash, Michelle; Sulfab, Maisoun; Tian, Yang; Hung, Magdeleine; Fung, Wanchi; Vivian, Randall W.; Trenkle, James; Taylor, James; Bjornson, Kyla; Bondy, Steven; Liu, Xiaohong; Link, John; Neyts, Johan; Sakowicz, Roman; Zhong, Weidong; Tang, Hengli; Schmitz, UliPLoS One (2012), 7 (6), e39163CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymic activity in biochem. assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chem. activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further anal. reveals that the aberrantly migrating NS5B species contains the inhibitor mol. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore anal. of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP-mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI) of the viral polymerase.(c) Leivers, M.; Miller, J. F.; Chan, S. A.; Lauchli, R.; Liehr, S.; Mo, W.; Ton, T.; Turner, E. M.; Youngman, M.; Falls, J. G.; Long, S.; Mathis, A.; Walker, J. Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism. J. Med. Chem. 2014, 57, 1964– 1975, DOI: 10.1021/jm401337x .(d) Powers, J. P.; Piper, D. E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J. M.; Jaen, J. C.; Lee, G.; Liu, J.; Peterson, M. G.; Tonn, G. R.; Ye, Q.; Walker, N. P. C.; Wang, Z. SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J. Med. Chem. 2006, 49, 1034– 1046, DOI: 10.1021/jm050859x[ACS Full Text
], [CAS], Google Scholar84dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XksV2ltA%253D%253D&md5=722ac0edb5dabb720e30475ef5925d5fSAR and Mode of Action of Novel Non-Nucleoside Inhibitors of Hepatitis C NS5b RNA PolymerasePowers, Jay P.; Piper, Derek E.; Li, Yang; Mayorga, Veronica; Anzola, John; Chen, James M.; Jaen, Juan C.; Lee, Gary; Liu, Jinqian; Peterson, M. Greg; Tonn, George R.; Ye, Qiuping; Walker, Nigel P. C.; Wang, ZhulunJournal of Medicinal Chemistry (2006), 49 (3), 1034-1046CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochem. potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were detd. by x-ray crystallog., and the inhibitors were found to bind in an allosteric binding site sep. from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compds. in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b. - 85Pinto, D. J.P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 2001, 44, 566– 578, DOI: 10.1021/jm000409z
- 86Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. MedChemComm 2011, 2, 669– 674, DOI: 10.1039/c1md00093d[Crossref], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotl2gt7o%253D&md5=3effbdd29832ac7b57eabbc26c66217bIntramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical spaceAlex, Alexander; Millan, David S.; Perez, Manuel; Wakenhut, Florian; Whitlock, Gavin A.MedChemComm (2011), 2 (7), 669-674CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Utilizing 'beyond rule of five' chem. space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramol. hydrogen bonds in drug mols. is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramol. hydrogen bonding in several 'beyond rule of five' oral drugs is described. Furthermore, the propensity for these drugs to form intramol. hydrogen bonds could be predicted for through modeling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramol. hydrogen bonding in these mols. is supported by intrinsic cell permeability and intestinal absorption data in rat and human.
- 87(a) Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of compounds. J. Med. Chem. 2012, 55, 4877– 4895, DOI: 10.1021/jm201136z[ACS Full Text.
], [CAS], Google Scholar87ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsFKlt7s%253D&md5=6c5dffbb11db6fa893ff3c50fe7778ccStructural Modifications that Alter the P-Glycoprotein Efflux Properties of CompoundsHitchcock, Stephen A.Journal of Medicinal Chemistry (2012), 55 (11), 4877-4895CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This perspective is focused on structural modifications and strategies that can be applied during compd. optimization in order to modulate the P-glycoprotein efflux properties of small mols. with a particular emphasis on implications for CNS penetration. The precise mol. interactions that confer P-glycoprotein efflux remain relatively poorly defined. The promiscuous nature of P-glycoprotein efflux renders the rational circumvention of efflux, while simultaneously optimizing compds. for eficacy, safety, and pharmacokinetic properties, an extremely challenging undertaking.(b) Desai, P. V.; Raub, T. J.; Blanco, M. J. How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg. Med. Chem. Lett. 2012, 22, 6540– 6548, DOI: 10.1016/j.bmcl.2012.08.059[Crossref], [PubMed], [CAS], Google Scholar87bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVSjsr%252FO&md5=a27f286d4349eec6f76b745b19ccf84fHow hydrogen bonds impact P-glycoprotein transport and permeabilityDesai, Prashant V.; Raub, Thomas J.; Blanco, Maria-JesusBioorganic & Medicinal Chemistry Letters (2012), 22 (21), 6540-6548CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. The requirement to cross a biol. membrane can be a complex process esp. if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramol. H-bonds to increase membrane permeability and/or decrease P-gp efflux. - 88(a) Dalvit, C.; Vulpetti, A. Intermolecular and intramolecular hydrogen bonds involving fluorine atoms: implications for recognition, selectivity, and chemical properties. ChemMedChem 2012, 7, 262– 272, DOI: 10.1002/cmdc.201100483[Crossref], [PubMed], [CAS], Google Scholar.88ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xps1CisA%253D%253D&md5=21efccc023f44ed600725e2a834222aeIntermolecular and Intramolecular Hydrogen Bonds Involving Fluorine Atoms: Implications for Recognition, Selectivity, and Chemical PropertiesDalvit, Claudio; Vulpetti, AnnaChemMedChem (2012), 7 (2), 262-272CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A correlation between 19F NMR isotropic chem. shift and close intermol. F···H-X contacts (with X = N or O) has been identified upon anal. of the X-ray crystal structures of fluorinated mols. listed in the Cambridge Structural Database (CSD). An optimal F···X distance involving primary and shielded secondary fluorine atoms in hydrogen-bond formation along with a correlation between F···H distance and F···H-X angle were also derived from the anal. The hydrogen bonds involving fluorine are relevant, not only for the recognition mechanism and stabilization of a preferred conformation, but also for improvement in the permeability of the mols., as shown with examples taken from a proprietary database. Results of an anal. of the small no. of fluorine-contg. natural products listed in the Protein Data Bank (PDB) appear to strengthen the derived correlation between 19F NMR isotropic chem. shift and interactions involving fluorine (also known as the "rule of shielding") and provides a hypothesis for the recognition mechanism and catalytic activity of specific enzymes. Novel chem. scaffolds, based on the rule of shielding, have been designed for recognizing distinct structural motifs present in proteins. It is envisaged that this approach could find useful applications in drug design for the efficient optimization of chem. fragments or promising compds. by increasing potency and selectivity against the desired biomol. target.(b) Dalvit, C.; Invernizzi, C.; Vulpetti, A. Fluorine as a hydrogen-bond acceptor: experimental evidence and computational calculations. Chem. - Eur. J. 2014, 20, 11058– 11068, DOI: 10.1002/chem.201402858[Crossref], [PubMed], [CAS], Google Scholar88bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyqsb3F&md5=c46aba69b8dcf928f00806b5e51bae54Fluorine as a Hydrogen-Bond Acceptor: Experimental Evidence and Computational CalculationsDalvit, Claudio; Invernizzi, Christian; Vulpetti, AnnaChemistry - A European Journal (2014), 20 (35), 11058-11068CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Hydrogen-bonding interactions play an important role in many chem. and biol. systems. Fluorine acting as a hydrogen-bond acceptor in intermol. and intramol. interactions was the subject of many controversial discussions and there are different opinions about it. Recently, the authors proposed a correlation between the propensity of fluorine to be involved in hydrogen bonds and its 19F NMR chem. shift. The authors now provide addnl. exptl. and computational evidence for this correlation. The strength of hydrogen-bond complexes involving the fluorine moieties CH2F, CHF2, and CF3 was measured and characterized in simple systems by using established and novel NMR methods and compared to the known hydrogen-bond complex formed between acetophenone and p-fluorophenol. Implications of these results for 19F NMR screening are analyzed. Computed values of the mol. electrostatic potential at the different fluorine atoms and the anal. of the electron d. topol. at bond crit. points correlate well with the NMR results.
- 89Weiss, M. M.; Williamson, T.; Babu-Khan, S.; Bartberger, M. D.; Brown, J.; Chen, K.; Cheng, Y.; Citron, M.; Croghan, M. D.; Dineen, T. A.; Esmay, J.; Graceffa, R. F.; Harried, S. S.; Hickman, D.; Hitchcock, S. A.; Horne, D. B.; Huang, H.; Imbeah-Ampiah, R.; Judd, T.; Kaller, M. R.; Kreiman, C. R.; La, D. S.; Li, V.; Lopez, P.; Louie, S.; Monenschein, H.; Nguyen, T. T.; Pennington, L. D.; Rattan, C.; San Miguel, T.; Sickmier, E. A.; Wahl, R. C.; Wen, P. H.; Wood, S.; Xue, Q.; Yang, B. H.; Patel, V. F.; Zhong, W. Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid. J. Med. Chem. 2012, 55, 9009– 9024, DOI: 10.1021/jm300119p
- 90Swahn, B.-M.; Kolmodin, K.; Karlström, S.; von Berg, S.; Söderman, P.; Holenz, J.; Berg, S.; Lindström, J.; Sundström, M.; Turek, D.; Kihlström, J.; Slivo, C.; Andersson, L.; Pyring, D.; Rotticci, D.; Öhberg, L.; Kers, A.; Bogar, K.; von Kieseritzky, F.; Bergh, M.; Olsson, L.-L.; Janson, J.; Eketjäll, S.; Georgievska, B.; Jeppsson, F.; Fälting, J. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J. Med. Chem. 2012, 55, 9346– 9361, DOI: 10.1021/jm3009025[ACS Full Text
], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1OmtL%252FM&md5=da7685d90f56449caa77b6e6393e0a7dDesign and Synthesis of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of β-Amyloid PeptidesSwahn, Britt-Marie; Kolmodin, Karin; Karlstroem, Sofia; von Berg, Stefan; Soederman, Peter; Holenz, Joerg; Berg, Stefan; Lindstroem, Johan; Sundstroem, Marie; Turek, Dominika; Kihlstroem, Jacob; Slivo, Can; Andersson, Lars; Pyring, David; Rotticci, Didier; Oehberg, Liselotte; Kers, Annika; Bogar, Krisztian; Bergh, Margareta; Olsson, Lise-Lotte; Janson, Juliette; Eketjaell, Susanna; Georgievska, Biljana; Jeppsson, Fredrik; Faelting, JohannaJournal of Medicinal Chemistry (2012), 55 (21), 9346-9361CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clin. candidate drug for Alzheimer's disease, (S)-32 (I, AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain redn. of Aβ40, is discussed. Due to the basic nature of these compds., they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 (II) and (R)-41 (III) showing large in vitro margins with BACE1 cell IC50 values of 8.6 and 0.16 nM, resp., and hERG IC50 values of 16 and 2.8 μM, resp. Several compds. were advanced into pharmacodynamic studies and demonstrated significant redn. of β-amyloid peptides in mouse brain following oral dosing. - 91Bell, I. M.; Bednar, R. A.; Fay, J. F.; Gallicchio, S. N.; Hochman, J. H.; McMasters, D. R.; Miller-Stein, C.; Moore, E. L.; Mosser, S. D.; Pudvah, N. T.; Quigley, A. G.; Salvatore, C. A.; Stump, C. A.; Theberge, C. R.; Wong, B. K.; Zartman, C. B.; Zhang, X. F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 6165– 6169, DOI: 10.1016/j.bmcl.2006.09.045[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtF2jsr%252FL&md5=55d47a7297cf5ab82fa7bac62a22d98aIdentification of novel, orally bioavailable spirohydantoin CGRP receptor antagonistsBell, Ian M.; Bednar, Rodney A.; Fay, John F.; Gallicchio, Steven N.; Hochman, Jerome H.; McMasters, Daniel R.; Miller-Stein, Cynthia; Moore, Eric L.; Mosser, Scott D.; Pudvah, Nicole T.; Quigley, Amy G.; Salvatore, Christopher A.; Stump, Craig A.; Theberge, Cory R.; Wong, Bradley K.; Zartman, C. Blair; Zhang, Xu-Fang; Kane, Stefanie A.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.Bioorganic & Medicinal Chemistry Letters (2006), 16 (24), 6165-6169CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)A rapid analog approach to identification of spirohydantoin-based CGRP antagonists provided novel, low mol. wt. leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compd. 12 (I), a potent CGRP receptor antagonist (Ki = 21 nM) with good oral bioavailability in three species.
- 92Koshizawa, T.; Morimoto, T.; Watanabe, G.; Watanabe, T.; Yamasaki, N.; Sawada, Y.; Fukuda, T.; Okuda, A.; Shibuya, K.; Ohgiya, T. Optimization of a novel series of potent and orally bioavailable GPR119 agonists. Bioorg. Med. Chem. Lett. 2017, 27, 3249– 3253, DOI: 10.1016/j.bmcl.2017.06.034[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVGms7zF&md5=e0cf277df0c16ba2c9100f52722f406dOptimization of a novel series of potent and orally bioavailable GPR119 agonistsKoshizawa, Tomoaki; Morimoto, Toshiharu; Watanabe, Gen; Watanabe, Toshiaki; Yamasaki, Nao; Sawada, Yoshikazu; Fukuda, Tomoaki; Okuda, Ayumu; Shibuya, Kimiyuki; Ohgiya, TadaakiBioorganic & Medicinal Chemistry Letters (2017), 27 (15), 3249-3253CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50 = 129 nM) was improved by replacing the intramol. hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compd. 12 (EC50 = 53 nM). Optimized compd. 26, which was identified by the further optimization of 12, exhibited potent activity (EC50 = 42 nM) with improved clearance in liver microsomes and induced a 33% redn. in blood glucose area under the curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice.
- 93Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure. J. Med. Chem. 2008, 51, 4858– 4861, DOI: 10.1021/jm800546t[ACS Full Text
], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVyrsb4%253D&md5=2256020d2b940d4c52fb59c6e51b2343Discovery of (R)-4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): A Potent Antagonist of the Human Calcitonin Gene-Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal ExposureDegnan, Andrew P.; Chaturvedula, Prasad V.; Conway, Charles M.; Cook, Deborah A.; Davis, Carl D.; Denton, Rex; Han, Xiaojun; Macci, Robert; Mathias, Neil R.; Moench, Paul; Pin, Sokhom S.; Ren, Shelly X.; Schartman, Richard; Signor, Laura J.; Thalody, George; Widmann, Kimberly A.; Xu, Cen; Macor, John E.; Dubowchik, Gene M.Journal of Medicinal Chemistry (2008), 51 (16), 4858-4861CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chem. leads suffered from modest potency, significant CYP3A4 inhibition, and poor aq. soly. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a mol. with outstanding potency, a favorable predictive toxicol. profile, and remarkable aq. soly. Compd. 4 has good intranasal bioavailablity in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models. - 94Razgulin, A. V.; Mecozzi, S. Binding properties of aromatic carbon-bound fluorine. J. Med. Chem. 2006, 49, 7902– 7906, DOI: 10.1021/jm0600702
- 95(a) Lewis, R. T.; Blackaby, W. P.; Blackburn, T.; Jennings, A. S. R.; Pike, A.; Wilson, R. A.; Hallett, D. J.; Cook, S. M.; Ferris, P.; Marshall, G. R.; Reynolds, D. S.; Sheppard, W. F. A.; Smith, A. J.; Sohal, B.; Stanley, J.; Tye, S. J.; Wafford, K. A.; Atack, J. R. A pyridazine series of α2/α3 subtype selective GABAA agonists for the treatment of anxiety. J. Med. Chem. 2006, 49, 2600– 2610, DOI: 10.1021/jm051144x .(b) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett, D.; Merchant, K. J.; Thomas, S. R. 8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor. Bioorg. Med. Chem. Lett. 2006, 16, 1518– 1522, DOI: 10.1016/j.bmcl.2005.12.037[Crossref], [PubMed], [CAS], Google Scholar95bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1ynurY%253D&md5=e923a5a430fdc343a64cac7b175a31998-Fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptorHumphries, Alexander C.; Gancia, Emanuela; Gilligan, Myra T.; Goodacre, Simon; Hallett, David; Merchant, Kevin J.; Thomas, Steve R.Bioorganic & Medicinal Chemistry Letters (2006), 16 (6), 1518-1522CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochem. mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochem. mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 2'-fluoro-5'-[8-fluoro-7-(2-hydroxy-2-propyl)imidazo[1,2-a]pyridin-3-yl]biphenyl-2-carbonitrile acts as a bioisosteric replacement for imidazopyrimidine in the GABAA receptor modulator 2'-fluoro-5'-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile.
- 96(a) Robarge, K. D.; Lee, W.; Eigenbrot, C.; Ultsch, M.; Wiesmann, C.; Heald, R.; Price, S.; Hewitt, J.; Jackson, P.; Savy, P.; Burton, B.; Choo, E. F.; Pang, J.; Boggs, J.; Yang, A.; Yang, X.; Baumgardner, M. Structure based design of novel 6,5 heterocbicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a]pyrazine G-479. Bioorg. Med. Chem. Lett. 2014, 24, 4714– 4723, DOI: 10.1016/j.bmcl.2014.08.008
- 97(a) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Yang, X.; Richards, M.; Shipps, G. W., Jr. Discovery of a novel series of CHK1 kinase inhibitors with a distinctive hinge binding mode. ACS Med. Chem. Lett. 2012, 3, 123– 128, DOI: 10.1021/ml200249h[ACS Full Text.
], [CAS], Google Scholar97ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpslGntQ%253D%253D&md5=0033fbe5837cc4c6287c4a5428665247Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding ModeHuang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Yang, Xianshu; Richards, Matthew; Shipps, Gerald W.ACS Medicinal Chemistry Letters (2012), 3 (2), 123-128CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection-mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.(b) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Richards, M.; Tadikonda, P. K.; Reddy, P. A.; Zhao, L.; Siddiqui, M. A.; Parry, D.; Davis, N.; Seghezzi, W.; Wiswell, D.; Shipps, G. W., Jr. Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2590– 2594, DOI: 10.1016/j.bmcl.2013.02.108[Crossref], [PubMed], [CAS], Google Scholar97bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksFars7o%253D&md5=f9288637d69888cf8a808eb72897ba70Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitorsHuang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Richards, Matthew; Tadikonda, Praveen K.; Reddy, Panduranga Adulla; Zhao, Lianyun; Arshad Siddiqui, M.; Parry, David; Davis, Nicole; Seghezzi, Wolfgang; Wiswell, Derek; Shipps, Gerald W.Bioorganic & Medicinal Chemistry Letters (2013), 23 (9), 2590-2594CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)N-(Piperazinylaryl) amino- and heterocyclyl-substituted thiazolecarboxamides such as N-(piperazinylpyridinyl) (oxoisoindolinyl)thiazolecarboxamide I were prepd. as selective inhibitors of checkpoint kinase 1 (CHK1). Both the identities of the amino substituent on the thiazole ring and the aryl ring connecting the piperazine moiety to the thiazolecarboxamide were varied to det. the structure-activity relationship for enzymic and cellular CHK1 inhibition and for selectivity over the related kinase CHK2. I inhibited CHK1 with IC50 values against the enzyme and against cells of 1 nM and 30 nM, resp., with > 104 selectivity for CHK1 over CHK2; the inhibition of CYP 3A4, 2D6, and 2C9 in human liver microsomes, of hERG in various assays, and of other kinases and of various G protein-coupled receptors by I was detd. The structure of a complex of I with CHK1 was detd. by X-ray crystallog.; the topol. of its binding to the ATP-binding site of CHK1 is detd. - 98(a) Koller, A. N.; Božilović, J.; Engels, J. W.; Gohlke, H. Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs. Nucleic Acids Res. 2010, 38, 3133– 3146, DOI: 10.1093/nar/gkp1237[Crossref], [PubMed], [CAS], Google Scholar.98ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFyktbY%253D&md5=c13d7b313f142d43b366fe82f4affa71Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogsKoller, Alrun N.; Bozilovic, Jelena; Engels, Joachim W.; Gohlke, HolgerNucleic Acids Research (2010), 38 (9), 3133-3146CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)The thermodn. of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estd. by potential of mean force calcns. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol-1. Decompg. the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol-1 compared to non-fluorinated analogs. This is attributed to stabilizing C-F...H-N dipolar interactions and stronger N...H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-Methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first exptl. evidence for nitrogen-contg. heterocylces as bioisosteres of arom. rings bearing fluorine atoms.(b) Gohlke, H.; Božilović, J.; Engels, J. W. Synthesis and properties of fluorinated nucleobases in DNA and RNA. Mol. Medicine Med. Chem. 2012, 6, 3– 32, DOI: 10.1142/9781848166363_0001[Crossref], [CAS], Google Scholar98bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1CitbvF&md5=401399b94327a1d01accc6a736983282Synthesis and properties of fluorinated nucleobases in DNA and RNAGohlke, Holger; Bozilovic, Jelena; Engels, Joachim W.Molecular Medicine and Medicinal Chemistry (2012), 6 (Fluorine in Pharmaceutical and Medicinal Chemistry), 3-32CODEN: MMMCCE ISSN:. (Imperial College Press)A review with refs. Synthesis and crystallog. studies of fluorinated non-polar nucleoside isosteres and thermodn. analyses and computer simulations of model DNA and RNAs incorporating them are reviewed.
- 99(a) Giroud, M.; Harder, M.; Kuhn, B.; Haap, W.; Trapp, N.; Schweizer, W. B.; Schirmeister, T.; Diederich, F. Fluorine scan of inhibitors of the cysteine protease human cathepsin L: dipolar and quadrupolar effects in the π-stacking of fluorinated phenyl rings on peptide amide bonds. ChemMedChem 2016, 11, 1042– 1047, DOI: 10.1002/cmdc.201600132[Crossref], [PubMed], [CAS], Google Scholar.99ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtlSit7o%253D&md5=298c19d0abfdee7fa7c9593b21da62f0Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide BondsGiroud, Maude; Harder, Michael; Kuhn, Bernd; Haap, Wolfgang; Trapp, Nils; Schweizer, W. Bernd; Schirmeister, Tanja; Diederich, FrancoisChemMedChem (2016), 11 (10), 1042-1047CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chem. calcns. In the exptl. study, the Ph substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by addnl. interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calcns. strongly support the contributions of the mol. quadrupole moments of the fluorinated Ph rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.(b) Giroud, M.; Ivkovic, J.; Martignoni, M.; Fleuti, M.; Trapp, N.; Haap, W.; Kuglstatter, A.; Benz, J.; Kuhn, B.; Schirmeister, T.; Diederich, F. Inhibition of the cysteine protease human cathepsin L by triazine nitriles: amide···heteroarene π-stacking interactions and chalcogen bonding in the S3 pocket. ChemMedChem 2017, 12, 257– 270, DOI: 10.1002/cmdc.201600563[Crossref], [PubMed], [CAS], Google Scholar99bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlyisw%253D%253D&md5=c8515e2082b8874cfd943b0ff61a6510Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide···Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 PocketGiroud, Maude; Ivkovic, Jakov; Martignoni, Mara; Fleuti, Marianne; Trapp, Nils; Haap, Wolfgang; Kuglstatter, Andreas; Benz, Joerg; Kuhn, Bernd; Schirmeister, Tanja; Diederich, FrancoisChemMedChem (2017), 12 (3), 257-270CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene···peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory consts. (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroarom. ligands feature enhanced binding by comparison with hydrocarbon analogs. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nM) and benzothiazolyl (Ki=17 nM) ligands was enhanced by intermol. C-S···O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
- 100Császár, P.; Császár, A. On the dipole moments of fluorobenzenes by quantum chemical methods. J. Mol. Struct.: THEOCHEM 1984, 110, 405– 407, DOI: 10.1016/0166-1280(84)80090-1
- 101van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.; Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russell, M. G. N.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.; Castro, J. L. Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles. J. Med. Chem. 1999, 42, 2087– 2104, DOI: 10.1021/jm981133m[ACS Full Text
], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnvVymtro%253D&md5=2cc155335a622de308f285e470f7b570Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(1-piperazinyl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profilesvan Niel, Monique B.; Collins, Ian; Beer, Margaret S.; Broughton, Howard B.; Cheng, Susan K. F.; Goodacre, Simon C.; Heald, Anne; Locker, Karen L.; MacLeod, Angus M.; Morrison, Denise; Moyes, Christopher R.; O'Connor, Desmond; Pike, Andrew; Rowley, Michael; Russel, N.; Sohal, Balbinder; Stanton, Josephine A.; Thomas, Steven; Verrier, Hugh; Watt, Alan P.; Castro, Jose L.Journal of Medicinal Chemistry (1999), 42 (12), 2087-2104CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)It has previously been reported that a 3-(3-(1-piperazinyl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal, versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivs. with one or two fluorines in the Pr linker were developed. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compds., and this redn. of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted. - 102(a) Paulini, R.; Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788– 1805, DOI: 10.1002/anie.200462213[Crossref], [CAS], Google Scholar.102ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXislWkt7s%253D&md5=6ad842547313b27fc1676e9c3a001909Orthogonal multipolar interactions in structural chemistry and biologyPaulini, Ralph; Mueller, Klaus; Diederich, FrancoisAngewandte Chemie, International Edition (2005), 44 (12), 1788-1805CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The past few decades of mol. recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biol. receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A no. of illustrative examples of these interactions found in X-ray crystal structures of small mols. and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chem. and biol. mol. recognition processes.(b) Xing, L.; Keefer, C.; Brown, M. F. Fluorine multipolar interaction: towards elucidating its energetics in binding recognition. J. Fluorine Chem. 2017, 198, 47– 53, DOI: 10.1016/j.jfluchem.2016.12.013[Crossref], [CAS], Google Scholar102bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlartg%253D%253D&md5=9dedd4fdc6214090960005fc33375ef2Fluorine multipolar interaction: Toward elucidating its energetics in binding recognitionXing, Li; Keefer, Christopher; Brown, Matthew F.Journal of Fluorine Chemistry (2017), 198 (), 47-53CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)Multipolar interactions have gained attention due to their roles in mol. recognition events of chem. and biol. systems. Structural evidence suggests that the fluorine multipolar interaction is a favorable mol. interaction in the paradigm of protein-ligand recognition. With an aim to understand its propensity and energetics in ligand-protein assembly, the authors mined the "Pfizer protein-ligand x-ray structure database" with three-dimensional constraints for the presence of such interactions. A set of transformation rules were applied to generate their corresponding matched mol. pairs (MMPs) that bear hydrogen(s) in place of the interacting fluorine(s). Biol. activities were retrieved from the authors' internal data warehouse for the MMPs with and without the ability to form the multipolar interaction. On the basis of the obsd. potency differences the authors detd. that the free energy gain assocd. with the fluorine multipolar interaction is relatively modest, ∼0.3-0.6 kcal/mol, and the net impact on lipophilic efficiency (LipE) is essentially neutral. A general guideline for medicinal chemists has emerged from this study, enabling a more rational employment of this type of interaction in mol. design.
- 103(a) Shi, A.; Murai, M. J.; He, S.; Lund, G.; Hartley, T.; Purohit, T.; Reddy, G.; Chruszcz, M.; Grembecka, J.; Cierpicki, T. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 2012, 120, 4461– 4469, DOI: 10.1182/blood-2012-05-429274[Crossref], [PubMed], [CAS], Google Scholar.103ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVWgtb7J&md5=c1ab14816cf5ea3590fe03b0ed405ea5Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemiaShi, Aibin; Murai, Marcelo J.; He, Shihan; Lund, George; Hartley, Thomas; Purohit, Trupta; Reddy, Gireesh; Chruszcz, Maksymilian; Grembecka, Jolanta; Cierpicki, TomaszBlood (2012), 120 (23), 4461-4469CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Menin functions as a crit. oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resoln. crystal structure of human menin in complex with a small-mol. inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compd. binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compd. that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-mol. inhibitor.(b) Pollock, J.; Borkin, D.; Lund, G.; Purohit, T.; Dyguda-Kazimierowicz, E.; Grembecka, J.; Cierpicki, T. Rational design of orthogonal multipolar interactions with fluorine in protein–ligand complexes. J. Med. Chem. 2015, 58, 7465– 7474, DOI: 10.1021/acs.jmedchem.5b00975[ACS Full Text.
], [CAS], Google Scholar103bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOju73F&md5=56d54cdfbf8af7d68666572a57335c51Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand ComplexesPollock, Jonathan; Borkin, Dmitry; Lund, George; Purohit, Trupta; Dyguda-Kazimierowicz, Edyta; Grembecka, Jolanta; Cierpicki, TomaszJournal of Medicinal Chemistry (2015), 58 (18), 7465-7474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Multipolar interactions involving fluorine and the protein backbone have been frequently obsd. in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to the high affinity of small mol. inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogs by systematically changing the no. of fluorine atoms, and we detd. high-resoln. crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin-MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine-backbone interactions in protein-ligand complexes, we developed a computational algorithm named FMAP, which calcs. fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Anal. of the menin-MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine-backbone interactions may represent a particularly attractive approach to improve inhibitors of protein-protein interactions.(c) Grembecka, J.; He, S.; Shi, A.; Purohit, T.; Muntean, A. G.; Sorenson, R. J.; Showalter, H. D.; Murai, M. J.; Belcher, A. M.; Hartley, T.; Hess, J. L.; Cierpicki, T. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 2012, 8, 277– 284, DOI: 10.1038/nchembio.773[Crossref], [PubMed], [CAS], Google Scholar.103chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlOrsrY%253D&md5=55eb9f353031dfef4c1a281b0ac28cbaMenin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemiaGrembecka, Jolanta; He, Shihan; Shi, Aibin; Purohit, Trupta; Muntean, Andrew G.; Sorenson, Roderick J.; Showalter, Hollis D.; Murai, Marcelo J.; Belcher, Amalia M.; Hartley, Thomas; Hess, Jay L.; Cierpicki, TomaszNature Chemical Biology (2012), 8 (3), 277-284CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-mol. inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compds. effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compds. provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.(d) Borkin, D.; Pollock, J.; Kempinska, K.; Purohit, T.; Li, X.; Wen, B.; Zhao, T.; Miao, H.; Shukla, S.; He, M.; Sun, D.; Cierpicki, T.; Grembecka, J. Property focused structure-based optimization of small molecule inhibitors of the protein–protein interaction between menin and mixed lineage leukemia (MLL). J. Med. Chem. 2016, 59, 892– 913, DOI: 10.1021/acs.jmedchem.5b01305[ACS Full Text
], [CAS], Google Scholar103dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XltFersw%253D%253D&md5=f89b6eda72671f133a38181b3b23632dProperty Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)Borkin, Dmitry; Pollock, Jonathan; Kempinska, Katarzyna; Purohit, Trupta; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Miao, Hongzhi; Shukla, Shirish; He, Miao; Sun, Duxin; Cierpicki, Tomasz; Grembecka, JolantaJournal of Medicinal Chemistry (2016), 59 (3), 892-913CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Development of potent small mol. inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compds., which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compd. 1 (MI-136) to identify compds. suitable for in vivo studies in mice. This work resulted in the identification of compd. 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications. - 104(a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.; D’Arcy, A.; Stihle, M.; Müller, K.; Diederich, F. A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F···C═O interactions. Angew. Chem., Int. Ed. 2003, 42, 2507– 2511, DOI: 10.1002/anie.200351268[Crossref], [CAS], Google Scholar.104ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXkvFCrt7k%253D&md5=f9851cb27f3e9d10152ad10abcd5c965A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: Evidence for C-F···C=O interactionsOlsen, Jacob A.; Banner, David W.; Seiler, Paul; Sander, Ulrike Obst; D'Arcy, Allan; Stihle, Martine; Mueller, Klaus; Diederich, FrancoisAngewandte Chemie, International Edition (2003), 42 (22), 2507-2511CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A highly fluorophilic environment comprising the H-Cα-C=O unit of Asn 98 in the active site of thrombin was identified by X-ray crystallog. of a complex formed between the enzyme and a synthetic inhibitor (see partial X-ray structure, distances are in Angstroms). Short C-F···H-Cα and C-F···C=O contacts involving H-Cα-C=O fragments were also frequently obsd. in small-mol. X-ray crystal structures.(b) Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.; Kansy, M.; Müller, K.; Diederich, F. Fluorine interactions at the thrombin active site: protein backbone fragments H-Cα-C═O comprise a favorable C-F environment and interactions of C-F with electrophiles. ChemBioChem 2004, 5, 666– 675, DOI: 10.1002/cbic.200300907[Crossref], [PubMed], [CAS], Google Scholar.104bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFeqtb8%253D&md5=1171f81bb64f9c04f849d3aaa63e5c27Fluorine interactions at the thrombin active site: Protein backbone fragments H-Cα-C=O comprise a favorable C-F environment and interactions of C-F with electrophilesOlsen, Jacob A.; Banner, David W.; Seiler, Paul; Wagner, Bjoern; Tschopp, Thomas; Obst-Sander, Ulrike; Kansy, Manfred; Mueller, Klaus; Diederich, FrancoisChemBioChem (2004), 5 (5), 666-675CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4-fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X-ray crystal-structure anal. of the protein-ligand complex revealed favorable C-F···H-Cα-C=O and C-F···C=O interactions of the 4-F substituent of the inhibitor with the backbone H-Cα-C=O unit of Asn98. The importance of these interactions was further corroborated by the anal. of small-mol. X-ray crystal-structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the C-F···C=O interactions that are obsd. for both arom. and aliph. C-F units and a variety of carbonyl and carboxyl derivs., the F atom approaches the C=O C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions C-F···C≡N, C-F···C-F1 and C-F···NO2, in which the F atoms interact at subvan der Waals distances with the electrophilic centers.(c) Schweizer, E.; Hoffmann-Röder, A.; Olsen, J. A.; Seiler, P.; Obst-Sander, U.; Wagner, B.; Kansy, M.; Banner, D. W.; Diederich, F. Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors. Org. Biomol. Chem. 2006, 4, 2364– 2375, DOI: 10.1039/B602585D
- 105Bauer, M. R.; Jones, R. N.; Baud, M. G. J.; Wilcken, R.; Boeckler, F. M.; Fersht, A. R.; Joerger, A. C.; Spencer, J. Harnessing fluorine-sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs. ACS Chem. Biol. 2016, 11, 2265– 2274, DOI: 10.1021/acschembio.6b00315[ACS Full Text
], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptlOgsbg%253D&md5=73f018ccf7a437efc42ea0cc4eb2843fHarnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue DrugsBauer, Matthias R.; Jones, Rhiannon N.; Baud, Matthias G. J.; Wilcken, Rainer; Boeckler, Frank M.; Fersht, Alan R.; Joerger, Andreas C.; Spencer, JohnACS Chemical Biology (2016), 11 (8), 2265-2274CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-mol. stabilizers of this mutant. One of these mols., PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temp. of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small mol. ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole Et anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol-1 atom-1). High-resoln. crystal structures of the Y220C-ligand complexes combined with quantum chem. calcns. revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells. - 106(a) Lou, Y.; Sweeney, Z. K.; Kuglstatter, A.; Davis, D.; Goldstein, D. M.; Han, X.; Hong, J.; Kocer, B.; Kondru, R. K.; Litman, R.; McIntosh, J.; Sarma, K.; Suh, J.; Taygerly, J.; Owens, T. D. Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s tyrosine kinase (BTK) inhibitor scaffold. Bioorg. Med. Chem. Lett. 2015, 25, 367– 371, DOI: 10.1016/j.bmcl.2014.11.030[Crossref], [PubMed], [CAS], Google Scholar.106ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitValtrvF&md5=e1f4815a0df9e91ce9150eacf196fc07Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffoldLou, Yan; Sweeney, Zachary K.; Kuglstatter, Andreas; Davis, Dana; Goldstein, David M.; Han, Xiaochun; Hong, Junbae; Kocer, Buelent; Kondru, Rama K.; Litman, Renee; McIntosh, Joel; Sarma, Keshab; Suh, Judy; Taygerly, Joshua; Owens, Timothy D.Bioorganic & Medicinal Chemistry Letters (2015), 25 (2), 367-371CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a satd. bicyclic ring system yields no apparent benefit, the same operation on an unsatd. bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent mols. and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.(b) Lou, Y.; Han, X.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth, M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.; Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.; Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D. Structure-based drug design of RN486, a potent and selective Bruton’s tyrosine kinase (BTK) Inhibitor, for the treatment of rheumatoid arthritis. J. Med. Chem. 2015, 58, 512– 516, DOI: 10.1021/jm500305p[ACS Full Text.
], [CAS], Google Scholar106bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsl2qtb8%253D&md5=dc3c069b0e876f44846a30e3aa6a894aStructure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid ArthritisLou, Yan; Han, Xiaochun; Kuglstatter, Andreas; Kondru, Rama K.; Sweeney, Zachary K.; Soth, Michael; McIntosh, Joel; Litman, Renee; Suh, Judy; Kocer, Buelent; Davis, Dana; Park, Jaehyeon; Frauchiger, Sandra; Dewdney, Nolan; Zecic, Hasim; Taygerly, Joshua P.; Sarma, Keshab; Hong, Junbae; Hill, Ronald J.; Gabriel, Tobias; Goldstein, David M.; Owens, Timothy D.Journal of Medicinal Chemistry (2015), 58 (1), 512-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alc. group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compd. I (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclin. characterization based on its favorable properties.(c) Lou, Y.; Lopez, F.; Jiang, Y.; Han, X.; Brotherton, C.; Billedeau, R.; Gabriel, S.; Gleason, S.; Goldstein, D. M.; Hilgenkamp, R.; Kocer, B.; Orzechowski, L.; Tan, J.; Wovkulich, P.; Wen, B.; Fry, D.; Di Lello, P.; Chen, L.; Zhang, F.-j.; Fretland, J.; Nangia, A.; Yang, T.; Owens, T. D. Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK). Bioorg. Med. Chem. Lett. 2017, 27, 632– 635, DOI: 10.1016/j.bmcl.2016.11.092[Crossref], [PubMed], [CAS], Google Scholar106chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFClt7zI&md5=55afd6fa4c4da934dfbe0654aaf5031dMitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK)Lou, Yan; Lopez, Francisco; Jiang, Yongying; Han, Xiaochun; Brotherton, Chris; Billedeau, Roland; Gabriel, Steve; Gleason, Shelly; Goldstein, David M.; Hilgenkamp, Ramona; Kocer, Buelent; Orzechowski, Lucja; Tan, Jenny; Wovkulich, Peter; Wen, Bo; Fry, David; Di Lello, Paola; Chen, Lucy; Zhang, Fang-jie; Fretland, Jennifer; Nangia, Anjali; Yang, Tian; Owens, Timothy D.Bioorganic & Medicinal Chemistry Letters (2017), 27 (3), 632-635CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a no. of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead mols. in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compd. 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation assocn. of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS anal. of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compd. 7 (RN941) with significantly reduced covalent binding of 26 pmol/mg protein. - 107Hao, G.-F.; Wang, F.; Li, H.; Zhu, X.-L.; Yang, W.-C.; Huang, L.-S.; Wu, J.-W.; Berry, E. A.; Yang, G.-F. Computational discovery of picomolar Qo site inhibitors of cytochrome bc1 complex. J. Am. Chem. Soc. 2012, 134, 11168– 11176, DOI: 10.1021/ja3001908[ACS Full Text
], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotlemtLo%253D&md5=23821de7aaecdbcb8aa513a05fd5bc87Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 ComplexHao, Ge-Fei; Wang, Fu; Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A.; Yang, Guang-FuJournal of the American Chemical Society (2012), 134 (27), 11168-11176CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A crit. challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophys. method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compd. 4 (Ki = 881.80 nM, porcine bc1), the most potent compd. 4f displayed 20 507-fold improved binding affinity (Ki = 43.00 pM). Compd. 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Addnl., the crystal structure of compd. 4e (Ki = 83.00 pM) bound to the chicken bc1 was detd. at 2.70 Å resoln., providing a mol. basis for understanding its ultrapotency. To the authors' knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophys. screening techniques. - 108García-LLinás, X.; Bauzá, A.; Seth, S. K.; Frontera, A. Importance of R-CF3•••O tetrel bonding interactions in biological systems. J. Phys. Chem. A 2017, 121, 5371– 5376, DOI: 10.1021/acs.jpca.7b06052
- 109Cisneros, J. A.; Robertson, M. J.; Valhondo, M.; Jorgensen, W. L. Irregularities in enzyme assays: the case of macrophage migration inhibitory factor. Bioorg. Med. Chem. Lett. 2016, 26, 2764– 2767, DOI: 10.1016/j.bmcl.2016.04.074[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFCqtLs%253D&md5=a232a355d251396f4d19e79954bf469bIrregularities in enzyme assays: The case of macrophage migration inhibitory factorCisneros, Jose A.; Robertson, Michael J.; Valhondo, Margarita; Jorgensen, William L.Bioorganic & Medicinal Chemistry Letters (2016), 26 (12), 2764-2767CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhibitors of human macrophage migration inhibitory factor (MIF) previously reported in the literature have been reexamd. by synthesis, assaying for tautomerase activity, and protein crystallog. Substantial inconsistencies between prior and current assay results are noted. They appear to arise from difficulties with the tautomerase substrates, soly. issues, and esp. covalent inhibition. Incubation time variation shows that several compds. are covalent or slow-binding inhibitors. Two protein crystal structures are provided; one confirms that a twice-discovered compd. is a covalent inhibitor.
- 110(a) Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; Yang, H.; Gross, S.; Artin, E.; Saada, V.; Mylonas, E.; Quivoron, C.; Popovici-Muller, J.; Saunders, J. O.; Salituro, F. G.; Yan, S.; Murray, S.; Wei, W.; Gao, Y.; Dang, L.; Dorsch, M.; Agresta, S.; Schenkein, D. P.; Biller, S. A.; Su, S. M.; de Botton, S.; Yen, K. E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013, 340, 622– 626, DOI: 10.1126/science.1234769[Crossref], [PubMed], [CAS], Google Scholar.110ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmslWksbs%253D&md5=fe3db6b043a8b31fb661d0bdbd75e19fTargeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular DifferentiationWang, Fang; Travins, Jeremy; De La Barre, Byron; Penard-Lacronique, Virginie; Schalm, Stefanie; Hansen, Erica; Straley, Kimberly; Kernytsky, Andrew; Liu, Wei; Gliser, Camelia; Yang, Hua; Gross, Stefan; Artin, Erin; Saada, Veronique; Mylonas, Elena; Quivoron, Cyril; Popovici-Muller, Janeta; Saunders, Jeffrey O.; Salituro, Francesco G.; Yan, Shunqi; Murray, Stuart; Wei, Wentao; Gao, Yi; Dang, Lenny; Dorsch, Marion; Agresta, Sam; Schenkein, David P.; Biller, Scott A.; Su, Shinsan M.; de Botton, Stephane; Yen, Katharine E.Science (Washington, DC, United States) (2013), 340 (6132), 622-626CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A no. of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small mol., AGI-6780, that potently and selectively inhibits the tumor-assocd. mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymol. anal. were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.(b) Yen, K.; Travins, J.; Wang, F.; David, M. D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; Chen, Y.; Nagaraja, R.; Choe, S.; Jin, L.; Konteatis, Z.; Cianchetta; Saunders, J. O.; Salituro, F. G.; Quivoron, C.; Opolon, P.; Bawa, O.; Saada, O.; Paci, A.; Broutin, S.; Bernard, O. A.; de Botton, S.; Marteyn, B. S.; Pilichowska, M.; Xu, Y. X.; Fang, C.; Jiang, F.; Wei, W.; Jin, S.; Silverman, L.; Liu, W.; Yang, H.; Dang, L.; Dorsch, M.; Penard-Lacronique, V.; Biller, S. A.; Su, S.-S. M. AG-221, A first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discovery 2017, 7, 478– 493, DOI: 10.1158/2159-8290.CD-16-1034[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFemurY%253D&md5=b83b3d82491d02befbde03aa392a6914AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 MutationsYen, Katharine; Travins, Jeremy; Wang, Fang; David, Muriel D.; Artin, Erin; Straley, Kimberly; Padyana, Anil; Gross, Stefan; De La Barre, Byron; Tobin, Erica; Chen, Yue; Nagaraja, Raj; Choe, Sung; Jin, Lei; Konteatis, Zenon; Cianchetta, Giovanni; Saunders, Jeffrey O.; Salituro, Francesco G.; Quivoron, Cyril; Opolon, Paule; Bawa, Olivia; Saada, Veronique; Paci, Angelo; Broutin, Sophie; Bernard, Olivier A.; de Botton, Stephane; Marteyn, Benoit S.; Pilichowska, Monika; Xu, Ying Xia; Fang, Cheng; Jiang, Fan; Wei, Wentao; Jin, Shengfang; Silverman, Lee; Liu, Wei; Yang, Hua; Dang, Lenny; Dorsch, Marion; Penard-Lacronique, Virginie; Biller, Scott A.; Su, Shin-San MichaelCancer Discovery (2017), 7 (5), 478-493CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematol. and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG prodn. and induced cellular differentiation in primary human IDH2 mutation-pos. acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clin. trials of AG-221 in patients with IDH2 mutation-pos. advanced hematol. malignancies. Significance: Mutations in IDH1/2 are identified in approx. 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclin. models and induces differentiation of malignant blasts, supporting its clin. development.
- 111Bhatia, C.; Yue, W. W.; Niesen, F.; Pilka, E.; Ugochukwu, E.; Savitsky, P.; Hozjan, V.; Roos, A. K.; Filippakopoulos, P.; Von Delft, F.; Heightman, T.; Arrowsmith, C.; Weigelt, J.; Edwards, A.; Bountra, C.; Opperman, U. 2WM3: Crystal structure of NmrA-like family domain containing protein 1 in complex with niflumic acid. Protein Data Bank, 2009, DOI: DOI: 10.2210/pdb2wm3/pdb .
- 112Blobaum, A. L.; Uddin, Md. J.; Felts, A. S.; Crews, B. C.; Rouzer, C. A.; Marnett, L. J. The 2′-trifluoromethyl analogue of indomethacin is a potent and selective COX-2 inhibitor. ACS Med. Chem. Lett. 2013, 4, 486– 490, DOI: 10.1021/ml400066a
- 113Sun, L.-Q.; Mull, E.; Zheng, B.; D’Andrea, S.; Zhao, Q.; Wang, A. X.; Sin, N.; Venables, B. L.; Sit, S.-Y.; Chen, Y.; Chen, J.; Cocuzza, A.; Bilder, D. M.; Mathur, A.; Rampulla, R.; Chen, B.-C.; Palani, T.; Ganesan, S.; Arunachalam, P. N.; Falk, P.; Levine, A.; Chen, C.; Friborg, J.; Yu, F.; Hernandez, D.; Sheaffer, A. K.; Knipe, J. O.; Han, Y.-H.; Schartman, R.; Donoso, M.; Mosure, K.; Sinz, M. W.; Zvyaga, T.; Rajamani, R.; Kish, K.; Tredup, J.; Klei, H. E.; Gao, Q.; Ng, A.; Mueller, L.; Grasela, D. M.; Adams, S.; Loy, J.; Levesque, P. C.; Sun, H.; Shi, H.; Sun, L.; Warner, W.; Li, D.; Zhu, J.; Wang, Y.-K.; Fang, H.; Cockett, M. I.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Discovery of a potent acyclic, tripeptidic, acyl sulfonamide inhibitor of hepatitis C virus NS3 protease as a back-up to asunaprevir with the potential for once-daily dosing. J. Med. Chem. 2016, 59, 8042– 8060, DOI: 10.1021/acs.jmedchem.6b00821[ACS Full Text
], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtl2rsrnK&md5=9d87037fcf23ef830e7ea02a6c6f2f8bDiscovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily DosingSun, Li-Qiang; Mull, Eric; Zheng, Barbara; D'Andrea, Stanley; Zhao, Qian; Wang, Alan Xiangdong; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Chen, Jie; Cocuzza, Anthony; Bilder, Donna M.; Mathur, Arvind; Rampulla, Richard; Chen, Bang-Chi; Palani, Theerthagiri; Ganesan, Sivakumar; Arunachalam, Pirama Nayagam; Falk, Paul; Levine, Steven; Chen, Chaoqun; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Sheaffer, Amy K.; Knipe, Jay O.; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W.; Zvyaga, Tatyana; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Ng, Alicia; Mueller, Luciano; Grasela, Dennis M.; Adams, Stephen; Loy, James; Levesque, Paul C.; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Wang, Ying-Kai; Fang, Hua; Cockett, Mark I.; Meanwell, Nicholas A.; McPhee, Fiona; Scola, Paul M.Journal of Medicinal Chemistry (2016), 59 (17), 8042-8060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir is described. The objective of this work was the identification of a drug with antiviral properties and toxicol. parameters similar to asunaprevir, but with a preclin. pharmacokinetic (PK) profile that was predictive of once-daily dosing. Crit. to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compds. that, like asunaprevir, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 from clin. trials. Structure-activity relationships (SARs) at each of the structural subsites in asunaprevir were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Addnl. modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 I. - 114(a) Phillips, M. A.; Gujjar, R.; Malmquist, N. A.; White, J.; El Mazouni, F.; Baldwin, J.; Rathod, P. K. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite, Plasmodium falciparum. J. Med. Chem. 2008, 51, 3649– 3653, DOI: 10.1021/jm8001026[ACS Full Text.
], [CAS], Google Scholar114ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXms1Gisbs%253D&md5=7bdbdc57d346ef3290623adc4aed89eeTriazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite Plasmodium falciparumPhillips, Margaret A.; Gujjar, Ramesh; Malmquist, Nicholas A.; White, John; El Mazouni, Farah; Baldwin, Jeffrey; Rathod, Pradipsinh K.Journal of Medicinal Chemistry (2008), 51 (12), 3649-3653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor I that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogs were produced by an inexpensive three-step synthesis, and the series showed good assocn. between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).(b) Gujjar, R.; Marwaha, A.; El Mazouni, F.; White, J.; White, K. L.; Creason, S.; Shackleford, D. M.; Baldwin, J.; Charman, W. N.; Buckner, F. S.; Charman, S.; Rathod, P. K.; Phillips, M. A. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem. 2009, 52, 1864– 1872, DOI: 10.1021/jm801343r[ACS Full Text.
], [CAS], Google Scholar114bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtlenuro%253D&md5=773ca17ea78a4f833c092c211c90c199Identification of a Metabolically Stable Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Antimalarial Activity in MiceGujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah; White, John; White, Karen L.; Creason, Sharon; Shackleford, David M.; Baldwin, Jeffrey; Charman, William N.; Buckner, Frederick S.; Charman, Susan; Rathod, Pradipsinh K.; Phillips, Margaret A.Journal of Medicinal Chemistry (2009), 52 (7), 1864-1872CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compds. contg. naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metab. in human liver microsomes and which showed prolonged exposure in mice. Compd. 21 (DSM74), contg. p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.(c) Deng, X.; Gujjar, R.; El Mazouni, F.; Kaminsky, W.; Malmquist, N. A.; Goldsmith, E. J.; Rathod, P. K.; Phillips, M. A. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J. Biol. Chem. 2009, 284, 26999– 27009, DOI: 10.1074/jbc.M109.028589[Crossref], [PubMed], [CAS], Google Scholar.114chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFCgsL%252FM&md5=0b6b089104abafd748010651b964494eStructural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffoldsDeng, Xiaoyi; Gujjar, Ramesh; El Mazouni, Farah; Kaminsky, Werner; Malmquist, Nicholas A.; Goldsmith, Elizabeth J.; Rathod, Pradipsinh K.; Phillips, Margaret A.Journal of Biological Chemistry (2009), 284 (39), 26999-27009CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure detn. of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chem. classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small mol. crystallog., is that the triazolopyrimidines populate a resonance form that promotes charge sepn. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.(d) Coteron, J. M.; Marco, M.; Esquivias, J.; Deng, X.; White, K. L.; White, J.; Koltun, M.; El Mazouni, F.; Kokkonda, S.; Katneni, K.; Bhamidipati, R.; Shackleford, D. M.; Angulo-Barturen, I.; Ferrer, S. B.; Jiménez-Díaz, M. B.; Gamo, F.-J.; Goldsmith, E. J.; Charman, W. N.; Bathurst, I.; Floyd, D.; Matthews, D.; Burrows, J. N.; Rathod, P. K.; Charman, S. A.; Phillips, M. A. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J. Med. Chem. 2011, 54, 5540– 5561, DOI: 10.1021/jm200592f[ACS Full Text.
], [CAS], Google Scholar114dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXovVehsbg%253D&md5=d92f71aeda04fbbbbcd8905a657df011Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate PotentialCoteron, Jose M.; Marco, Maria; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L.; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M.; Angulo-Barturen, Inigo; Ferrer, Santiago B.; Jimenez-Diaz, Maria Belen; Gamo, Francisco-Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A.Journal of Medicinal Chemistry (2011), 54 (15), 5540-5561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chem. program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compd. has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compd. toward clin. candidate status.(e) Deng, X.; Kokkonda, S.; El Mazouni, F.; White, J.; Burrows, J. N.; Kaminsky, W.; Charman, S. A.; Matthews, D.; Rathod, P. K.; Phillips, M. A. Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J. Med. Chem. 2014, 57, 5381– 5394, DOI: 10.1021/jm500481t[ACS Full Text.
], [CAS], Google Scholar114ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXns1Chs74%253D&md5=abfc8df6c8510665049e65338732acf0Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase InhibitorsDeng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah; White, John; Burrows, Jeremy N.; Kaminsky, Werner; Charman, Susan A.; Matthews, David; Rathod, Pradipsinh K.; Phillips, Margaret A.Journal of Medicinal Chemistry (2014), 57 (12), 5381-5394CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. The authors describe a detailed anal. of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. The authors show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. The authors conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. The authors' studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.(f) Phillips, M. A.; Lotharius, J.; Marsh, K.; White, J.; Dayan, A.; White, K. L.; Njoroge, J. W.; El Mazouni, F.; Lao, Y.; Kokkonda, S.; Tomchick, D. R.; Deng, X.; Laird, T.; Bhatia, S. N.; March, S.; Ng, C. L.; Fidock, D. A.; Wittlin, S.; Lafuente-Monasterio, M.; Benito, F. J.; Alonso, L. M.; Martinez, M. S.; Jimenez-Diaz, M. B.; Bazaga, S. F.; Angulo-Barturen, I.; Haselden, J. N.; Louttit, J.; Cui, Y.; Sridhar, A.; Zeeman, A. M.; Kocken, C.; Sauerwein, R.; Dechering, K.; Avery, V. M.; Duffy, S.; Delves, M.; Sinden, R.; Ruecker, A.; Wickham, K. S.; Rochford, R.; Gahagen, J.; Iyer, L.; Riccio, E.; Mirsalis, J.; Bathhurst, I.; Rueckle, T.; Ding, X.; Campo, B.; Leroy, D.; Rogers, M. J.; Rathod, P. K.; Burrows, J. N.; Charman, S. A. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl. Med. 2015, 7 (296), 296ra111, DOI: 10.1126/scitranslmed.aaa6645 .(g) Phillips, M. A.; White, K. L.; Kokkonda, S.; Deng, X.; White, J.; El Mazouni, F.; Marsh, K.; Tomchick, D. R.; Manjalanagara, K.; Rudra, K. R.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Shackleford, D. M.; Chiu, F. C. K. M.; Campbell, M.; Jimenez-Diaz, M. B.; Ferrer Bazaga, S.; Angulo-Barturen, I.; Santos Martinez, M.; Lafuente-Monasterio, M.; Kaminsky, W.; Silue, K.; Zeeman, A.-M.; Kocken, C.; Leroy, D.; Blasco, B.; Rossignol, E.; Rueckle, T.; Matthews, D.; Burrows, J. N.; Waterson, D.; Palmer, M. J.; Rathod, P. K.; Charman, S. A. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect. Dis. 2016, 2, 945– 957, DOI: 10.1021/acsinfecdis.6b00144[ACS Full Text
], [CAS], Google Scholar114ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWmtbjJ&md5=df58b9d21b75ad84d6181d42a2341e60A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of MalariaPhillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Shackleford, David M.; Chiu, Francis C. K.; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Inigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N.; Waterson, David; Palmer, Michael J.; Rathod, Pradipsinh K.; Charman, Susan A.ACS Infectious Diseases (2016), 2 (12), 945-957CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor I of the Plasmodium enzyme is currently in clin. development. With the goal of identifying a backup compd. to I, the authors explored replacement of the SF5-aniline moiety of I with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of II, which has improved soly., lower intrinsic clearance and increased plasma exposure after oral dosing compared to I, while maintaining a long predicted human half-life. Its improved phys. and chem. properties will allow it to be formulated more readily than I. II showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly II showed equal activity against both P. falciparum and P. vivax field isolates, while I was more active on P. falciparum. II has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclin. development candidate. - 115Martin, M. P.; Zhu, J.-Y.; Lawrence, H. R.; Pireddu, R.; Luo, Y.; Alam, R.; Ozcan, S.; Sebti, S. M.; Lawrence, N. J.; Schönbrunn, E. A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. ACS Chem. Biol. 2012, 7, 698– 706, DOI: 10.1021/cb200508b[ACS Full Text
], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xntlaguw%253D%253D&md5=af1e536bcfae58a76762e85f4b0b9829A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora AMartin, Mathew P.; Zhu, Jin-Yi; Lawrence, Harshani R.; Pireddu, Roberta; Luo, Yunting; Alam, Riazul; Ozcan, Sevil; Sebti, Said M.; Lawrence, Nicholas J.; Schonbrunn, ErnstACS Chemical Biology (2012), 7 (4), 698-706CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small mol. inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced-dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three-dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with elec. dipoles. - 116(a) Clark, J.; Perrin, D. D. Prediction of the strengths of organic bases. Q. Rev., Chem. Soc. 1964, 18, 295– 320, DOI: 10.1039/qr9641800295[Crossref], [CAS], Google Scholar.116ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXis1Cl&md5=5b4002e8c9f42ac111f5fc9730198a22Prediction of the strengths of organic basesClark, Jim; Perrin, D. D.(1964), 18 (3), 295-320 ISSN:.A review with 44 references.(b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059[Crossref], [PubMed], [CAS], Google Scholar116bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFemsbY%253D&md5=478b70744312c01d3a43cf435d9598dePredicting and tuning physicochemical properties in lead optimization: amine basicitiesMorgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, KlausChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
- 117Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R. Application of the Goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: balancing pKa and steric effects in the optimization of 3-methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-fluorination. J. Med. Chem. 2006, 49, 2939– 2952, DOI: 10.1021/jm051262k[ACS Full Text
], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjsVajtb4%253D&md5=468ae2a5832e69d751628ca743ef951cApplication of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-FluorinationGrunewald, Gary L.; Seim, Mitchell R.; Lu, Jian; Makboul, Mariam; Criscione, Kevin R.Journal of Medicinal Chemistry (2006), 49 (10), 2939-2952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α2-adrenoceptor. Fluorination of the Me group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a redn. in affinity for the α2-adrenoceptor. However, increased fluorination also results in a redn. in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochem. evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the α2-adrenoceptor, while the latter were devoid of α2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity vs. the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency vs. the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the α2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α2-adrenoceptor. This seems to be the first successful use of the β-fluorination of aliph. amines to impart selectivity to a pharmacol. agent while maintaining potency at the site of interest. - 118Spahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017, 355, 966– 969, DOI: 10.1126/science.aai8636[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsVCgs7k%253D&md5=719809495aec8c3ac9e60429c9edea98A nontoxic pain killer designed by modeling of pathological receptor conformationsSpahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C.Science (Washington, DC, United States) (2017), 355 (6328), 966-969CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathol. (rather than physiol.) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissocn. const., selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissocn. by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
- 119(a) Cox, C. D.; Coleman, P. J.; Breslin, M. J.; Whitman, D. B.; Garbaccio, R. M.; Fraley, M. E.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Lobell, R. B.; Tao, W.; Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber, H. E.; Torrent, M.; Prueksaritanont, T.; Li, C.; Slaughter, D. E.; Mahan, E.; Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J. Med. Chem. 2008, 51, 4239– 4252, DOI: 10.1021/jm800386y[ACS Full Text.
], [CAS], Google Scholar119ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsl2rs7s%253D&md5=283d7227309cbe634f18a640c8085090Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory CancerCox, Christopher D.; Coleman, Paul J.; Breslin, Michael J.; Whitman, David B.; Garbaccio, Robert M.; Fraley, Mark E.; Buser, Carolyn A.; Walsh, Eileen S.; Hamilton, Kelly; Schaber, Michael D.; Lobell, Robert B.; Tao, Weikang; Davide, Joseph P.; Diehl, Ronald E.; Abrams, Marc T.; South, Vicki J.; Huber, Hans E.; Torrent, Maricel; Prueksaritanont, Thomayant; Li, Chunze; Slaughter, Donald E.; Mahan, Elizabeth; Fernandez-Metzler, Carmen; Yan, Youwei; Kuo, Lawrence C.; Kohl, Nancy E.; Hartman, George D.Journal of Medicinal Chemistry (2008), 51 (14), 4239-4252CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations assocd. with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compds. from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that β-fluorination modulated the pKa of the piperidine nitrogen and reduced Pgp efflux, but the resulting compd. (14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compd. 30 that has an optimal in vitro and metabolic profile. Compd. 30 (MK-0731) was recently studied in a phase I clin. trial in patients with taxane-refractory solid tumors.(b) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein. Bioorg. Med. Chem. Lett. 2007, 17, 2697– 2702, DOI: 10.1016/j.bmcl.2007.03.006 - 120McDonald, I. M.; Mate, R. A.; Zusi, F. C.; Huang, H.; Post-Munson, D. J.; Ferrante, M. A.; Gallagher, L.; Bertekap, R. L., Jr.; Knox, R. J.; Robertson, B. J.; Harden, D. G.; Morgan, D. G.; Lodge, N. J.; Dworetzky, S. I.; Olson, R. E.; Macor, J. E. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists. Bioorg. Med. Chem. Lett. 2013, 23, 1684– 1688, DOI: 10.1016/j.bmcl.2013.01.070
- 121Sun, H.; Xia, M.; Shahane, S. A.; Jadhav, A.; Austin, C. P.; Huang, R. Are hERG channel blockers also phospholipidosis inducers?. Bioorg. Med. Chem. Lett. 2013, 23, 4587– 4590, DOI: 10.1016/j.bmcl.2013.06.034[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFShu73M&md5=20f829eba492b0380eadb33ebe5bb179Are hERG channel blockers also phospholipidosis inducers?Sun, Hongmao; Xia, Menghang; Shahane, Sampada A.; Jadhav, Ajit; Austin, Christopher P.; Huang, RuiliBioorganic & Medicinal Chemistry Letters (2013), 23 (16), 4587-4590CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Both pharmacophore models of the human ether-a-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/pos. charged center, so it is interesting to investigate the overlap between the ligand chem. spaces of both targets. The authors have assayed over 4000 non-redundant drug-like compds. for both their hERG inhibitory activity and PLD inducing potential in a quant. high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compds. identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compds. were pos. charged. Among the 48 compds. that induced PLD without inhibiting hERG channel, 24 compds. (50.0%) carried steroidal structures. According to the authors' results, hERG channel blockers and PLD inducers share a large chem. space. In addn., a pos. charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.
- 122Nakajima, Y.; Inoue, T.; Nakai, K.; Mukoyoshi, K.; Hamaguchi, H.; Hatanaka, K.; Sasaki, H.; Tanaka, A.; Takahashi, F.; Kunikawa, S.; Usuda, H.; Moritomo, A.; Higashi, Y.; Inami, M.; Shirakami, S. Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3. Bioorg. Med. Chem. 2015, 23, 4871– 4883, DOI: 10.1016/j.bmc.2015.05.034[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFOktrc%253D&md5=378ff172c2374ea40d784c59f1e192d7Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3Nakajima, Yutaka; Inoue, Takayuki; Nakai, Kazuo; Mukoyoshi, Koichiro; Hamaguchi, Hisao; Hatanaka, Keiko; Sasaki, Hiroshi; Tanaka, Akira; Takahashi, Fumie; Kunikawa, Shigeki; Usuda, Hiroyuki; Moritomo, Ayako; Higashi, Yasuyuki; Inami, Masamichi; Shirakami, ShoheiBioorganic & Medicinal Chemistry (2015), 23 (15), 4871-4883CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivs. are promising candidates for treating such diseases. In chem. modification of lead compd. (I), the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addn., modulation of phys. properties such as mol. lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. The authors' optimization study gave compd. 31 (4-[[(3S,4R)-1-(5-cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide), which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
- 123Rombouts, F. J. R.; Tresadern, G.; Delgado, O.; Martínez-Lamenca, C.; Van Gool, M.; García-Molina, A.; Alonso de Diego, S. A.; Oehlrich, D.; Prokopcova, H.; Alonso, J. M.; Austin, N.; Borghys, H.; Van Brandt, S.; Surkyn, M.; De Cleyn, M.; Vos, A.; Alexander, R.; Macdonald, G.; Moechars, D.; Gijsen, H.; Trabanco, A. A. 1,4-Oxazine β-secretase 1 (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads. J. Med. Chem. 2015, 58, 8216– 8235, DOI: 10.1021/acs.jmedchem.5b01101[ACS Full Text
], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFWktL3L&md5=d3563a26a17a1c86c45a4f99b18be2511,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant LeadsRombouts, Frederik J. R.; Tresadern, Gary; Delgado, Oscar; Martinez-Lamenca, Carolina; Van Gool, Michiel; Garcia-Molina, Aranzazu; Alonso de Diego, Sergio A.; Oehlrich, Daniel; Prokopcova, Hana; Alonso, Jose Manuel; Austin, Nigel; Borghys, Herman; Van Brandt, Sven; Surkyn, Michel; De Cleyn, Michel; Vos, Ann; Alexander, Richard; Macdonald, Gregor; Moechars, Dieder; Gijsen, Harrie; Trabanco, Andres A.Journal of Medicinal Chemistry (2015), 58 (20), 8216-8235CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)1,4-Oxazines are presented, which show good in vitro inhibition in enzymic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and esp. P-glycoprotein efflux. This led to compds. which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, resp., in mouse and dog models. The amyloid lowering potential of these mols. makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease. - 124Scattolin, T.; Deckers, K.; Schoenebeck, F. Efficient synthesis of trifluoromethyl amines through a formal umpolung strategy from the bench-stable precursor (Me4N)SCF3. Angew. Chem., Int. Ed. 2017, 56, 221– 224, DOI: 10.1002/anie.201609480[Crossref], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVGqtr7E&md5=5c26bd9e2281d4e3ecd33bbdeb6a087aEfficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3Scattolin, Thomas; Deckers, Kristina; Schoenebeck, FranziskaAngewandte Chemie, International Edition (2017), 56 (1), 221-224CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Reported herein is the one-pot synthesis of trifluoromethylated amines at room temp. using the bench-stable (Me4N)SCF3 reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3 with the amine, giving quant. formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug mols.
- 125Asahina, Y.; Araya, I.; Iwase, K.; Iinuma, F.; Hosaka, M.; Ishizaki, T. Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent. J. Med. Chem. 2005, 48, 3443– 3446, DOI: 10.1021/jm040204g
- 126Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma, A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang, X.; Wick, M. M.; Zhang, X.; Lum, R. T. Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg. Med. Chem. Lett. 1997, 7, 2697– 2702, DOI: 10.1016/S0960-894X(97)10076-2
- 127Miao, Z.; Zhu, L.; Dong, G.; Zhuang, C.; Wu, Y.; Wang, S.; Guo, Z.; Liu, Y.; Wu, S.; Zhu, S.; Fang, K.; Yao, J.; Li, J.; Sheng, C.; Zhang, W. A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors. J. Med. Chem. 2013, 56, 7902– 7910, DOI: 10.1021/jm400906z[ACS Full Text
], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFarsrzE&md5=c99ef47778bdea1041e131efdb8fdbfaA New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S) 21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I InhibitorsMiao, Zhenyuan; Zhu, Lingjian; Dong, Guoqiang; Zhuang, Chunlin; Wu, Yuelin; Wang, Shengzheng; Guo, Zizao; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Fang, Kun; Yao, Jianzhong; Li, Jian; Sheng, Chunquan; Zhang, WannianJournal of Medicinal Chemistry (2013), 56 (20), 7902-7910CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Lactone is a common structural motif in biol. active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin deriv., (20S,21S)-7-Cyclohexyluorocamptothecin, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. The authors' results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone. - 128Wipf, P.; Henninger, T. C.; Geib, S. J. Methyl- and (trifluoromethyl)alkene peptide isosteres: synthesis and evaluation of their potential as β-turn promoters and peptide mimetics. J. Org. Chem. 1998, 63, 6088– 6089, DOI: 10.1021/jo981057v[ACS Full Text
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- 130Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies. Org. Biomol. Chem. 2007, 5, 1151– 1157, DOI: 10.1039/b701559c[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvVakurc%253D&md5=64147d262b88033f13559044af6815ffChiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studiesCouve-Bonnaire, Samuel; Cahard, Dominique; Pannecoucke, XavierOrganic & Biomolecular Chemistry (2007), 5 (8), 1151-1157CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The replacement of the amide bond in a peptide backbone is a promising strategy in peptidomimetic drug research. Over the various amide bond surrogates, the fluoroolefin moiety has been successfully developed as an effective mimic. Today, fluorine-contg. compds. account for a large proportion of new active mols. in life sciences. The synthesis of fluoroolefin peptide mimics is not a trivial task and innovative approaches often need to be addressed, in particular for the stereocontrol of the double bond configuration and the chiral centers adjacent to the fluoroalkene. These fluorinated peptidomimetics have been synthesized and evaluated as metabolically stable and/or conformationally constrained analogs of enzyme inhibitors, and as tools for probing the function, structure, and binding process of receptors.
- 131Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T. H.; Blais, V.; Guérin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-ψ[(Z)CF═CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimetic. ACS Chem. Neurosci. 2017, 8, 40– 49, DOI: 10.1021/acschemneuro.6b00163[ACS Full Text
], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSisLnI&md5=893e2b2d560b04eebac0139a6830c42bSynthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimeticNadon, Jean-Francois; Rochon, Kristina; Grastilleur, Sebastien; Langlois, Guillaume; Dao, Thi Thanh Ha; Blais, Veronique; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.ACS Chemical Neuroscience (2017), 8 (1), 40-49CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepd. and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF=CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane exts. of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the elec. induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biol. activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes. - 132Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A. Synthesis and opioid activity of Tyr1-Ψ(Z)CF═CH]-Gly2 and Tyr1-Ψ(S)/(R)CF3CH-NH]-Gly2 Leu enkephalin fluorinated peptidomimetics. ChemMedChem 2017, 12, 571– 576, DOI: 10.1002/cmdc.201700103
- 133Rogers, M. T. The electric moments of some unsaturated aldehydes, ethers and halogen compounds. J. Am. Chem. Soc. 1947, 69, 1243– 1246, DOI: 10.1021/ja01198a003
- 134(a) Kobayakawa, T.; Narumi, T.; Tamamura, H. Remote stereoinduction in the organocuprate-mediated allylic alkylation of allylic gem-dichlorides: highly diastereoselective synthesis of (Z)-chloroalkene dipeptide isosteres. Org. Lett. 2015, 17, 2302– 2305, DOI: 10.1021/acs.orglett.5b00611 .(b) Waelchli, R.; Gamse, R.; Bauer, W.; Lier, E.; Feyen, J. H. M. Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogues of hPTH(1–36) fragment. Bioorg. Med. Chem. Lett. 1996, 6, 1151– 1156, DOI: 10.1016/0960-894X(96)00188-6[Crossref], [CAS], Google Scholar.134bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjsVCnurg%253D&md5=e1071148ed8dd3c0d0b32d3e6fc1bfb4Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogs of hPTH(1-36) fragmentWaelchli, Rudolf; Gamse, Rainer; Bauer, Wilfried; Meigel, Harald; Lier, Edouard; Feyen, Jean H. M.Bioorganic & Medicinal Chemistry Letters (1996), 6 (10), 1151-1156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)A series of human parathyroid hormone (1-36) [hPTH(1-36)] analogs were prepd. to study the role of the first peptide bond between residues Ser1-Val2. Some of these analogs were found to show high affinity binding in intact opossum kidney (OK-1) cells and were very active in their ability to stimulate adenylate cyclase prodn. in intact OK-1 cells, rat UMR-106-06 osteosarcoman cells and SaOS-2 human osteosarcoma cells.(c) Kobayakawa, T.; Matsuzaki, Y.; Hozumi, K.; Nomura, W.; Nomizu, M.; Tamamura, H. Synthesis of a Chloroalkene dipeptide isostere-containing peptidomimetic and its biological application. ACS Med. Chem. Lett. 2018, 9, 6– 10, DOI: 10.1021/acsmedchemlett.7b00234[ACS Full Text
], [CAS], Google Scholar134chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVeltrrO&md5=7840922bbd033792a553be95db17af3dSynthesis of a chloroalkene dipeptide isostere-containing peptidomimetic and its biological applicationKobayakawa, Takuya; Matsuzaki, Yudai; Hozumi, Kentaro; Nomura, Wataru; Nomizu, Motoyoshi; Tamamura, HirokazuACS Medicinal Chemistry Letters (2018), 9 (1), 6-10CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The first rapid and efficient chem. synthesis of a cyclic Arg-Gly-Asp (RGD) peptide contg. a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an N-Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-contg. cyclic RGD peptide was successful, and the synthesized CADI-contg. peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide. - 135Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry, N. A.; Weber, A. E. Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 2409– 2413, DOI: 10.1016/j.bmcl.2008.02.050[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjvFyktL0%253D&md5=09731e5d01cac5602e84baf81e10e890Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitorsEdmondson, Scott D.; Wei, Lan; Xu, Jinyou; Shang, Jackie; Xu, Shiyao; Pang, Jianmei; Chaudhary, Ashok; Dean, Dennis C.; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Patel, Reshma A.; Patel, Sangita B.; Scapin, Giovanna; Wu, Joseph K.; Beconi, Maria G.; Thornberry, Nancy A.; Weber, Ann E.Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2409-2413CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The synthesis, selectivity, rat pharmacokinetic profile, and drug metab. profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
- 136(a) Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics. Bioorg. Med. Chem. Lett. 2012, 22, 2938– 2942, DOI: 10.1016/j.bmcl.2012.02.051[Crossref], [PubMed], [CAS], Google Scholar.136ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktV2qtLk%253D&md5=513fc896ce045cbf1a236d75bb75b29cInhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimeticsChang, Wonsuk; Mosley, Ralph T.; Bansal, Shalini; Keilman, Meg; Lam, Angela M.; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2938-2942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-mol. hydrogen bonds were a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin contg. inhibitor exhibited picomolar activity (EC50 = 79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.(b) Belema, M.; Lopez, O. D.; Bender, J. A.; Romine, J. L.; St. Laurent, D. R.; Langley, D. R.; Lemm, J. A.; O’Boyle, D. R., II; Sun, J.-H.; Wang, C.; Fridell, R. A.; Meanwell, N. A. The discovery and development of hepatitis C virus NS5A replication complex inhibitors. J. Med. Chem. 2014, 57, 1643– 1672, DOI: 10.1021/jm401793m[ACS Full Text
], [CAS], Google Scholar136bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslygsbk%253D&md5=cc92046f9edcb633b433a0e6a4ac3fecDiscovery and Development of Hepatitis C Virus NS5A Replication Complex InhibitorsBelema, Makonen; Lopez, Omar D.; Bender, John A.; Romine, Jeffrey L.; St. Laurent, Denis R.; Langley, David R.; Lemm, Julie A.; O'Boyle, Donald R., II; Sun, Jin-Hua; Wang, Chunfu; Fridell, Robert A.; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2014), 57 (5), 1643-1672CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chem. studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compds. currently in clin. trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogs that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clin. trials with HCV NS5A RCIs. - 137Hollenstein, M.; Leumann, C. J. Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA. J. Org. Chem. 2005, 70, 3205– 3217, DOI: 10.1021/jo047753e[ACS Full Text
], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitVWrtLo%253D&md5=120463d7cacde3615181a5948949968fFluorinated Olefinic Peptide Nucleic Acid: Synthesis and Pairing Properties with Complementary DNAHollenstein, Marcel; Leumann, Christian J.Journal of Organic Chemistry (2005), 70 (8), 3205-3217CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The fluorinated olefinic peptide nucleic acid (F-OPA) system was designed as a peptide nucleic acid (PNA) analog in which the base carrying amide moiety was replaced by an isostructural and isoelectrostatic fluorinated C-C double bond, locking the nucleobases in one of the two possible rotameric forms. By comparison of the base-pairing properties of this analog with its nonfluorinated analog OPA and PNA, the authors attempted a closer understanding of the role of this amide function in complementary DNA recognition. Here, the synthesis of the F-OPA monomer building blocks contg. the nucleobases A, T, and G according to the MMTr/Acyl protecting group scheme is presented. Key steps are a selective desymmetrization of the double bond in the monomer precursor via lactonization as well as a highly regioselective Mitsunobu reaction for the introduction of the bases. PNA decamers contg. single F-OPA mutations and fully modified F-OPA decamers and pentadecamers contg. the bases A and T were synthesized by solid-phase peptide chem., and their hybridization properties with complementary parallel and antiparallel DNA were assessed by UV melting curves and CD spectroscopic methods. The stability of the duplexes formed by the decamers contg. single (Z)-F-OPA modifications with parallel and antiparallel DNA was found to be strongly dependent on their position in the sequence with Tm values ranging from +2.4 to -8.1°/modification as compared to PNA. Fully modified F-OPA decamers and pentadecamers were found to form parallel duplexes with complementary DNA with reduced stability compared to PNA or OPA. An asym. F-OPA pentadecamer was found to form a stable self-complex (Tm ∼ 65°) of unknown structure. The generally reduced affinity to DNA may therefore be due to an increased propensity for self-aggregation. - 138(a) Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R. M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J. Med. Chem. 2003, 46, 4050– 4062, DOI: 10.1021/jm030131l .(b) Parlow, J. J.; Stevens, A. M.; Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4297– 4312, DOI: 10.1021/jm030233b[ACS Full Text.
], [CAS], Google Scholar138bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1Kmsrg%253D&md5=1541bf4617e1a58623eb752b6417007eSynthesis and Crystal Structures of Substituted Benzenes and Benzoquinones as Tissue Factor VIIa InhibitorsParlow, John J.; Stevens, Anna M.; Stegeman, Roderick A.; Stallings, William C.; Kurumbail, Ravi G.; South, Michael S.Journal of Medicinal Chemistry (2003), 46 (20), 4297-4312CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Several multistep syntheses of substituted benzenes are reported. The benzene analogs were designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue Factor VIIa enzyme. A variety of chem. transformations including nucleophilic addns., reductive aminations, Stille couplings, and polymer-assisted soln.-phase (PASP) techniques were used to prep. key intermediates and final products. The initial analogs identified some weakly active compds. which ultimately led to a 340 nM (IC50) tissue Factor VIIa inhibitor with selectivity over other related enzymes. The structure-activity relationship of these inhibitors and the synthetic progression from the discovery of the lead compd. to the development of potent analogs will be discussed. The X-ray crystal structures of 3'-amino-N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide and N-[[4-(aminoiminomethyl)phenyl]methyl]-5-[(1-methylethyl)amino]-3,6-dioxo-2-phenyl-1,4-cyclohexadiene-1-acetamide inhibitors complexed with the TF/VIIa enzyme will also be described. Other compds. thus prepd. and screened included N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-2,6-difluoro-3-[[(phenylmethyl)sulfonyl]amino]benzeneacetamide.(c) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex. Bioorg. Med. Chem. Lett. 2003, 13, 3721– 3725, DOI: 10.1016/j.bmcl.2003.08.002 .(d) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4696– 4701, DOI: 10.1021/jm0301686[ACS Full Text
], [CAS], Google Scholar138dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1Kktrc%253D&md5=d463973a0ba48427f8131ae032c0637bDesign, Synthesis, and Crystal Structure of Selective 2-Pyridone Tissue Factor VIIa InhibitorsParlow, John J.; Kurumbail, Ravi G.; Stegeman, Roderick A.; Stevens, Anna M.; Stallings, William C.; South, Michael S.Journal of Medicinal Chemistry (2003), 46 (22), 4696-4701CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Targeted 2-pyridones were selected as tissue factor VIIa inhibitors and prepd. from 2,6-dibromopyridine via a multistep synthesis. A variety of chem. transformations, including regioselective nucleophilic addn., selective nitrogen alkylation, and a Suzuki coupling, afforded the targeted tissue factor VIIa inhibitors. The pyridone core was selected as a replacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue factor VIIa enzyme. These compds. were tested in several serine protease enzyme assays involved in the coagulation cascade exhibiting modest activity on tissue factor VIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structure of one inhibitor bound to tissue factor VIIa was obtained and will be described. Compds. thus prepd. and tested were 3-amino-5-[1-[2-[[[4-(aminoiminomethyl)phenyl]methyl]amino]-2-oxoethyl]-1,6-dihydro-5-[(1-methylethyl)amino]-6-oxo-2-pyridinyl]benzoic acid and N-[[4-(aminoiminomethyl)phenyl]methyl]-6-(3,5-diaminophenyl)-3-[(1-methylethyl)amino]-2-oxo-1(2H)-pyridineacetamide. - 139(a) Lee, L.; Kreutter, K. D.; Pan, W.; Crysler, C.; Spurlino, J.; Player, M. R.; Tomczuk, B.; Lu, T. 2-(2-Chloro-6-fluorophenyl)-acetamides as potent thrombin inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6266– 6269, DOI: 10.1016/j.bmcl.2007.09.013 .(b) Kreutter, K. D.; Lu, T.; Lee, L.; Giardino, E. C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.; Haertlein, B. J.; Mohan, V.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; McMillan, M.; Spurlino, J. C.; Huebert, N. D.; Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Player, M. R. Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg. Med. Chem. Lett. 2008, 18, 2865– 2870, DOI: 10.1016/j.bmcl.2008.03.087 .(c) Nantermet, P. G.; Burgey, C. S.; Robinson, K. A.; Pellicore, J. M.; Newton, C. L.; Deng, J. M.; Selnick, H. G.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Miller-Stein, C.; White, R. B.; Wong, B.; McMasters, D. R.; Wallace, A. A.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P.; Lyle, T. A. P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. Bioorg. Med. Chem. Lett. 2005, 15, 2771– 2775, DOI: 10.1016/j.bmcl.2005.03.110 .(d) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem. 2003, 46, 461– 473, DOI: 10.1021/jm020311f
- 140(a) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. The pKBHX database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. J. Med. Chem. 2009, 52, 4073– 4086, DOI: 10.1021/jm801331y[ACS Full Text.
], [CAS], Google Scholar140ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnsFKns7w%253D&md5=9ce4bea3e810752baba6ea5784b55ea0The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal ChemistsLaurence, Christian; Brameld, Ken A.; Graton, Jerome; Le Questel, Jean-Yves; Renault, EricJournal of Medicinal Chemistry (2009), 52 (14), 4073-4086CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The pKBHX database is presented, which corresponds to three main fields of data: hydrogen bond donor identification, thermodn. data and spectroscopic data. The pKBHX scale of hydrogen donor basicity differs considerable from the pKBH+ scale of proton transfer basicity. The hydrogen bond basicities of functional groups relevant to medicinal chem. and drug design is reviewed.(b) Kenny, P. W.; Montanari, C. A.; Prokopczyk, I. M.; Ribeiro, J. F.; Sartori, G. R. Hydrogen bond basicity prediction for medicinal chemistry design. J. Med. Chem. 2016, 59, 4278– 4288, DOI: 10.1021/acs.jmedchem.5b01946[ACS Full Text.
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Predictions are made for hydrogen bond basicity of fluorine in situations where relevant exptl. measurements are not available. It is shown how predicted pKBHX can be used to provide insight into the nature of bioisosterism and to profile heterocycles. Examples of pKBHX prediction for mol. structures with multiple, nonequivalent hydrogen bond acceptors are presented.(c) Pierce, A. C.; Sandretto, K. L.; Bemis, G. W. Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand binding. Proteins: Struct., Funct., Genet. 2002, 49, 567– 576, DOI: 10.1002/prot.10259[Crossref], [PubMed], [CAS], Google Scholar140chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XptlGru7c%253D&md5=641cc069501f9243df3ddc35cd3aa449Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand bindingPierce, Albert C.; Sandretto, Kathryn L.; Bemis, Guy W.Proteins: Structure, Function, and Genetics (2002), 49 (4), 567-576CODEN: PSFGEY; ISSN:0887-3585. (Wiley-Liss, Inc.)Although the hydrogen bond is known to be an important mediator of intermol. interactions, there has yet to be an anal. of the role of CH···O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of arom. ligands in 184 kinase crystal structures and 358 high-resoln. structures from the Protein Data Bank. CH groups adjacent to the pos. charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other arom. CH groups do not exhibit these characteristics. Ab initio calcns. reveal a considerable range of CH···O hydrogen bonding potentials among different arom. ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH···O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various arom. CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity anal. - 141Anilkumar, G. N.; Lesburg, C. A.; Selyutin, O.; Rosenblum, S. B.; Zeng, Q.; Jiang, Y.; Chan, T.-Y.; Pu, H.; Vaccaro, H.; Wang, L.; Bennett, F.; Chen, K. X.; Duca, J.; Gavalas, S.; Huang, Y.; Pinto, P.; Sannigrahi, M.; Velazquez, F.; Venkatraman, S.; Vibulbhan, B.; Agrawal, S.; Butkiewicz, N.; Feld, B.; Ferrari, E.; He, Z.; Jiang, C.-k.; Palermo, R. E.; Mcmonagle, P.; Huang, H.-C.; Shih, N.-Y.; Njoroge, G.; Kozlowski, J. A. I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles. Bioorg. Med. Chem. Lett. 2011, 21, 5336– 5341, DOI: 10.1016/j.bmcl.2011.07.021[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKis7zO&md5=0934657e3c8029bab0a01ea2c5113832I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocyclesAnilkumar, Gopinadhan N.; Lesburg, Charles A.; Selyutin, Oleg; Rosenblum, Stuart B.; Zeng, Qingbei; Jiang, Yueheng; Chan, Tin-Yau; Pu, Haiyan; Vaccaro, Henry; Wang, Li; Bennett, Frank; Chen, Kevin X.; Duca, Jose; Gavalas, Stephen; Huang, Yuhua; Pinto, Patrick; Sannigrahi, Mousumi; Velazquez, Francisco; Venkatraman, Srikanth; Vibulbhan, Bancha; Agrawal, Sony; Butkiewicz, Nancy; Feld, Boris; Ferrari, Eric; He, Zhiqing; Jiang, Chuan-kui; Palermo, Robert E.; McMonagle, Patricia; Huang, H.-C.; Shih, Neng-Yang; Njoroge, George; Kozlowski, Joseph A.Bioorganic & Medicinal Chemistry Letters (2011), 21 (18), 5336-5341CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead I (NS5B IC50 = 0.9 μM, replicon EC50 >100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in lead carboxyindoles II (NS5B IC50 = 0.032 μM, replicon EC50 = 1.4 μM) and III (NS5B IC50 = 0.017 μM, replicon EC50 = 0.3 μM) with improved enzyme and replicon activity.
- 142Adams, M. E.; Wallace, M. B.; Kanouni, T.; Scorah, N.; O’Connell, S. M.; Miyake, H.; Shi, L.; Halkowycz, P.; Zhang, L.; Dong, Q. Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy. Bioorg. Med. Chem. Lett. 2012, 22, 2411– 2414, DOI: 10.1016/j.bmcl.2012.02.026
- 143(a) Isshiki, Y.; Kohchi, Y.; Iikura, H.; Matsubara, Y.; Asoh, K.; Murata, T.; Kohchi, M.; Mizuguchi, E.; Tsujii, S.; Hattori, K.; Miura, T.; Yoshimura, Y.; Aida, S.; Miwa, M.; Saitoh, R.; Murao, N.; Okabe, H.; Belunis, C.; Janson, C.; Lukacs, C.; Schück, V.; Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg. Med. Chem. Lett. 2011, 21, 1795– 1801, DOI: 10.1016/j.bmcl.2011.01.062 .(b) Leijen, S.; Middleton, M. R.; Tresca, P.; Kraeber-Bodéré, F.; Dieras, V.; Scheulen, M. E.; Gupta, A.; Lopez-Valverde, V.; Xu, Z. X.; Rueger, R.; Tessier, J. J.; Shochat, E.; Blotner, S.; Naegelen, V. M.; Schellens, J. H.; Eberhardt, W. E. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin. Cancer Res. 2012, 18, 4794– 4805, DOI: 10.1158/1078-0432.CCR-12-0868[Crossref], [PubMed], [CAS], Google Scholar143bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ygsb%252FE&md5=ad4ba0b2d82d87158432fbd976fd536ePhase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid TumorsLeijen, Suzanne; Middleton, Mark R.; Tresca, Patricia; Kraeber-Bodere, Francoise; Dieras, Veronique; Scheulen, Max E.; Gupta, Avinash; Lopez-Valverde, Vanesa; Xu, Zhi-Xin; Rueger, Ruediger; Tessier, Jean J. L.; Shochat, Eliezer; Blotner, Steve; Naegelen, Valerie Meresse; Schellens, Jan H. M.; Eberhardt, Wilfried Ernst ErichClinical Cancer Research (2012), 18 (17), 4794-4805CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its max. tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-wk cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approx. 4 h. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clin. benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a redn. in fluorodeoxyglucose uptake by positron emission tomog. between baseline and day 15. Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794-805. ©2012 AACR.
- 144Ohren, J. F.; Chen, H.; Pavlovsky, A.; Whitehead, C.; Zhang, E.; Kuffa, P.; Yan, C.; McConnell, P.; Spessard, C.; Banotai, C.; Mueller, W. T.; Delaney, A.; Omer, C.; Sebolt-Leopold, J.; Dudley, D. T.; Leung, I. K.; Flamme, C.; Warmus, J.; Kaufman, M.; Barrett, S.; Tecle, H.; Hasemann, C. A. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 2004, 11, 1192– 1197, DOI: 10.1038/nsmb859[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVens7jM&md5=79ebbc2e3a9cdd3fbecb8bb35ea9dba3Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibitionOhren, Jeffrey F.; Chen, Huifen; Pavlovsky, Alexander; Whitehead, Christopher; Zhang, Erli; Kuffa, Peter; Yan, Chunhong; McConnell, Patrick; Spessard, Cindy; Banotai, Craig; Mueller, W. Thomas; Delaney, Amy; Omer, Charles; Sebolt-Leopold, Judith; Dudley, David T.; Leung, Iris K.; Flamme, Cathlin; Warmus, Joseph; Kaufman, Michael; Barrett, Stephen; Tecle, Haile; Hasemann, Charles A.Nature Structural & Molecular Biology (2004), 11 (12), 1192-1197CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)MEK1 and MEK2 kinases are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK MAP kinase (MAPK) signaling pathway. Approx. 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here, the authors present the x-ray crystal structures of human MEK1 and MEK2 kinases, each detd. as a ternary complex with MgATP and an inhibitor to a resoln. of 2.4 and 3.2 Å, resp. The structures revealed that MEK1 and MEK2 each had a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitors induced several conformational changes in the unphosphorylated MEK1 and MEK2 kinases that locked them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
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- 147(a) Nicolaou, I.; Zika, C.; Demopoulos, V. J. [1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a bioisostere of a carboxylic acid aldose reductase inhibitor. J. Med. Chem. 2004, 47, 2706– 2709, DOI: 10.1021/jm031060t .(b) Alexiou, P.; Demopoulos, V. J. A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity. J. Med. Chem. 2010, 53, 7756– 7766, DOI: 10.1021/jm101008m[ACS Full Text.
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- 154(a) Bégué, J.-P.; Bonnet-Delpon, D. Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives. ChemMedChem 2007, 2, 608– 624, DOI: 10.1002/cmdc.200600156[Crossref], [PubMed], [CAS], Google Scholar.154ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVGrurw%253D&md5=5caf9964669f5c3a54f1c250d187046aFluoroartemisinins: metabolically more stable antimalarial artemisinin derivativesBegue, Jean-Pierre; Bonnet-Delpon, DanieleChemMedChem (2007), 2 (5), 608-624CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This report is an overview on the design, prepn., and evaluation of metabolically stable artemisinins, using fluorine substitution. The chem. challenges encountered for the incorporation of fluorine-contg. elements and the prepn. of a large range of 10-trifluoromethyl artemisinin derivs. are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted. Preclin. data of lead compds., and evidence for their strong and prolonged antimalarial activity are presented.(b) Magueur, G.; Crousse, B.; Ourévitch, M.; Bonnet-Delpon, D.; Bégué, J.-P. Fluoro-artemisinins: when a gem-difluoroethylene replaces a carbonyl group. J. Fluorine Chem. 2006, 127, 637– 642, DOI: 10.1016/j.jfluchem.2005.12.013[Crossref], [CAS], Google Scholar154bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xksl2jsLY%253D&md5=842374feac786a3df37b48f55d21d776Fluoro-artemisinins: When a gem-difluoroethylene replaces a carbonyl groupMagueur, Guillaume; Crousse, Benoit; Ourevitch, Michele; Bonnet-Delpon, Daniele; Begue, Jean-PierreJournal of Fluorine Chemistry (2006), 127 (4-5), 637-642CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)Exo-gem-difluoromethylene-artemisinin (I) has been designed to mimic artemisinin. The classical Wittig olefination reaction applied to artemisinin failed. An alternative reaction involving the generation of an α-CF3 carbanion, from the corresponding bromide, allowed the access to the target compd. I, and could also be applied to the sugar series. The replacement of the carbonyl function by a difluoroethylene moiety resulted in a better antimalarial activity.
- 155(a) Tu, Y. Artemisinin- a gift from traditional Chinese medicine to the world (Nobel lecture). Angew. Chem., Int. Ed. 2016, 55, 10210– 10226, DOI: 10.1002/anie.201601967 .(b) Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.; Tracking Resistance to Artemisinin Collaboration Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 2014, 371, 411– 423, DOI: 10.1056/NEJMoa1314981[Crossref], [PubMed], [CAS], Google Scholar155bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1ers7jF&md5=bb2f2a4d554ba6a1f4c605868be43f6eSpread of artemisinin resistance in Plasmodium falciparum malariaAshley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.New England Journal of Medicine (2014), 371 (5), 411-423, 13 pp.CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)Background: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geog. extent of resistance is essential for planning containment and elimination strategies. Methods: Between May 2011 and Apr. 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kg of body wt. per day or 4 mg per kg, for 3 days, followed by a std. 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 h, and the parasite clearance half-lives were detd. Results: The median parasite clearance half-lives ranged from 1.9 h in the Democratic Republic of Congo to 7.0 h at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 h), strongly assocd. with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from Southern Vietnam to central Myanmar. The incidence of pre-treatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In Western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was assocd. with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Conclusions: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is assocd. with mutations in kelch13. Prolonged courses of artemisinin- based combination therapies are currently efficacious in areas where std. 3-day treatments are failing. (Funded by the U.K. Department of International Development and others).
- 156(a) Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.; Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D. M.; Verdoorn, T. A.; Bollini, S.; Vinitsky, A. 2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies. Org. Lett. 2001, 3, 3987– 3990, DOI: 10.1021/ol0166909[ACS Full Text.
], [CAS], Google Scholar156ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlKrtbs%253D&md5=1310c65ef4d6c86f4664654c554105f92-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural StudiesDubowchik, Gene M.; Vrudhula, Vivekananda M.; Dasgupta, Bireshwar; Ditta, Jonathan; Chen, Ti; Sheriff, Steven; Sipman, Karin; Witmer, Mark; Tredup, Jeffrey; Vyas, Dolatrai M.; Verdoorn, Todd A.; Bollini, Sagarika; Vinitsky, AlexanderOrganic Letters (2001), 3 (25), 3987-3990CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)2-Aryl-2,2-difluoroacetamido derivs. of proline and pipecolate esters I (X = F2, O, H2; Y = N, CH) and II (p = 1, 2; n = 2, 3; m = 0-3) are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 Ph ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.(b) Bollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A. High-throughput fluorescence polarization method for identification of FKBP12 ligands. J. Biomol. Screening 2002, 7, 526– 530, DOI: 10.1177/1087057102238626[Crossref], [PubMed], [CAS], Google Scholar156bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFemt7c%253D&md5=2bea4698dfb7153e0d2ef0eae4c637a5High-throughput fluorescence polarization method for identification of FKBP12 ligandsBollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A.Journal of Biomolecular Screening (2002), 7 (6), 526-530CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)FKBP12 is best known as the target of the widely used immunosuppressive drug FK506 but may also play a role in neuronal survival. Nonimmunosuppressive ligands of FKBP12 have been shown to have neuroprotective and neuroregenerative activity both in vitro and in vivo, stimulating interest in the development of high-throughput screens to rapidly identify novel ligands. FKBP12 was expressed as a His6-fusion in bacteria and purified by metal ion affinity and gel filtration chromatog. A high-throughput fluorescence polarization assay was developed to identify novel ligands of FKBP12. Dissocn. const. values of known FKBP12 ligands measured by the new method agreed closely with Ki values obtained by assaying inhibition of the rotamase activity of the enzyme. The fluorescence polarization assay is rapid, robust, and inexpensive and does not generate radioactive waste. It is very well suited for high-throughput screening efforts. - 157Ye, X. M.; Konradi, A. W.; Smith, J.; Aubele, D. L.; Garofalo, A. W.; Marugg, J.; Neitzel, M. L.; Semko, C. M.; Sham, H. L.; Sun, M.; Truong, A. P.; Wu, J.; Zhang, H.; Goldbach, E.; Sauer, J.-M.; Brigham, E. F.; Bova, M.; Basi, G. S. Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II). Bioorg. Med. Chem. Lett. 2010, 20, 3502– 3506, DOI: 10.1016/j.bmcl.2010.04.148[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntVCmsLg%253D&md5=712a8056390ea9663f0af178abc94712Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)Ye, Xiaocong M.; Konradi, Andrei W.; Smith, Jenifer; Aubele, Danielle L.; Garofalo, Albert W.; Marugg, Jennifer; Neitzel, Marty L.; Semko, Chris M.; Sham, Hing L.; Sun, Minghua; Truong, Anh P.; Wu, Jing; Zhang, Hongbin; Goldbach, Erich; Sauer, John-Michael; Brigham, Elizabeth F.; Bova, Michael; Basi, Guriqbal S.Bioorganic & Medicinal Chemistry Letters (2010), 20 (12), 3502-3506CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
- 158Xiamuxi, H.; Wang, Z.; Li, J.; Wang, Y.; Wu, C.; Yang, F.; Jiang, X.; Liu, Y.; Zhao, Q.; Chen, W.; Zhang, J.; Xie, Y.; Hu, T.; Xu, M.; Guo, S.; Akber Aisa, H.; He, Y.; Shen, J. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multi-receptor atypical antipsychotics. Bioorg. Med. Chem. 2017, 25, 4904– 4916, DOI: 10.1016/j.bmc.2017.07.040
- 159(a) Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J. Chem. 2004, 28, 1401– 1411, DOI: 10.1039/b405955g[Crossref], [CAS], Google Scholar.159ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVGqur3P&md5=7f40c026008b7e521e5a8d47cdc6c36cTrifluoromethyl group: an effective xenobiotic function for peptide backbone modificationZanda, MatteoNew Journal of Chemistry (2004), 28 (12), 1401-1411CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)A review. Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in the solid phase, for many different fluoroalkyl peptidomimetics, i.e., bis-trifluoromethyl (Tfm) analogs of Pepstatin A, which are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II; Tfm-malic peptidomimetics that are micromolar inhibitors of some matrix metalloproteinases; partially modified retro (PMR) and retro-inverso (PMRI) ψ[CH(CF3)NH] peptides with a strong proclivity to assume turn-like conformations; ψ[CH(CF3)NH] peptide mimics having a great potential as hybrids between natural peptides and hydrolytic transition state analogs; PMR peptides incorporating a trifluoroalanine surrogate. These novel classes of fluorinated peptide mimics are likely to represent just the tip of an iceberg formed by new peptidomimetic structures with unique biomedicinal and pharmaceutical properties.(b) Sani, M.; Volonterio, A.; Zanda, M. The trifluoroethylamine function as peptide bond replacement. ChemMedChem 2007, 2, 1693– 1700, DOI: 10.1002/cmdc.200700156[Crossref], [PubMed], [CAS], Google Scholar.159bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltlWlt7c%253D&md5=f319f5ec15482837b159ae6776302717The trifluoroethylamine function as peptide bond replacementSani, Monica; Volonterio, Alessandro; Zanda, MatteoChemMedChem (2007), 2 (12), 1693-1700CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Synthesis of peptidomimetics contg. a stereogenic trifluoroethylamine group in place of the peptide bond is discussed. Peptidomimetics contg. the trifluoroethylamine group in place of amide group have been found to be highly potent and metabolically stable inhibitors of cathepsin K.(c) Brusoe, A. T.; Hartwig, J. F. Palladium-catalyzed arylation of fluoroalkylamines. J. Am. Chem. Soc. 2015, 137, 8460– 8468, DOI: 10.1021/jacs.5b02512[ACS Full Text
], [CAS], Google Scholar159chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansrvF&md5=635a13908c88a8d23fb350d2ba6584bePalladium-Catalyzed Arylation of FluoroalkylaminesBrusoe, Andrew T.; Hartwig, John F.Journal of the American Chemical Society (2015), 137 (26), 8460-8468CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We report the synthesis of fluorinated anilines by palladium-catalyzed coupling of fluoroalkylamines with aryl bromides and aryl chlorides. The products of these reactions are valuable because anilines typically require the presence of an electron-withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidn., and the fluoroalkyl groups have steric properties and polarity distinct from those of more common electron-withdrawing amide and sulfonamide units. The fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base). However, the reactions conducted with the weaker base KOPh, which has rarely been used in cross-coupling to form C-N bonds, occurred in high yields in the presence of a catalyst derived from com. available AdBippyPhos and [Pd(allyl)Cl]2. Under these conditions, the reactions occur with low catalyst loadings (<0.50 mol % for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross-coupling reactions of aryl halides. The resting state of the catalyst is the phenoxide complex, [BippyPhosPd(Ar)OPh]; due to the electron-withdrawing property of the fluoroalkyl substituent, the turnover-limiting step of the reaction is reductive elimination to form the C-N bond. - 160(a) Volonterio, A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.; Bruche, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille, S. V.; Meli, M.; Ramirez de Arellano, C.; Zanda, M. Synthesis, structure and conformation of partially-modified retro- and retro-inverso Ψ[NHCH(CF3)]Gly peptides. Chem. - Eur. J. 2003, 9, 4510– 4522, DOI: 10.1002/chem.200304881[Crossref], [PubMed], [CAS], Google Scholar.160ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVygtb0%253D&md5=cba456e90602f8c832d751c3845db257Synthesis, structure and conformation of partially-modified retro- and retro-inverso ψ[NHCH(CF3)]Gly peptidesVolonterio, Alessandro; Bellosta, Stefano; Bravin, Fabio; Bellucci, Maria Cristina; Bruche, Luca; Colombo, Giorgio; Malpezzi, Luciana; Mazzini, Stefania; Meille, Stefano V.; Meli, Massimiliano; Ramirez de Arellano, Carmen; Zanda, MatteoChemistry - A European Journal (2003), 9 (18), 4510-4522CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Partially modified retro- (PMR) and retro-inverso (PMRI) ψ[NHCH(CF3)]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure α-amino esters and peptides with enantiomerically and geometrically pure N-(4,4,4-trifluorocrotonoyl)oxazolidin-2-ones. The factors underlying the obsd. moderate to good diastereocontrol have been investigated. The conformations of model PMR-ψ[NHCH(CF3)]Gly tripeptides have been studied in soln. by 1H NMR spectroscopy supported by MD calcns., as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: (1) severe torsional restrictions about sp3 bonds in the [CO-CH2-CH(CF3)-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF3 group and the R side chain and (2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl3 soln. and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramol. hydrogen bonding. The relative configuration of the -C*H(CF3)NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochem. X-ray diffraction and ab initio computational studies showed that the [-CH(CF3)NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analog, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF3)-NH-CH backbone angle close to 120°, C-CF3 bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O-)NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron d. on the CF3 group, tetrahedral backbone carbon).(b) Molteni, M.; Pesenti, C.; Sani, M.; Volonterio, A.; Zanda, M. Fluorinated peptidomimetics: synthesis, conformational and biological features. J. Fluorine Chem. 2004, 125, 1735– 1743, DOI: 10.1016/j.jfluchem.2004.09.014[Crossref], [CAS], Google Scholar.160bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVKrsbzP&md5=cb3388b61377efa640f6788c60df7109Fluorinated peptidomimetics: synthesis, conformational and biological featuresMolteni, Marco; Pesenti, Cristina; Sani, Monica; Volonterio, Alessandro; Zanda, MatteoJournal of Fluorine Chemistry (2004), 125 (11), 1735-1743CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Our interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in solid phase, for many different fluoroalkyl peptidomimetics, some of which are overviewed in this paper: (a) ψ[CH(CF3)NH]-peptide mimics holding a great potential as hybrids between natural peptides and hydrolytic transition state analogs, (b) trifluoromethyl (Tfm) malic peptidomimetics as micromolar inhibitors of some matrix metalloproteinases, and (c) bis-Tfm analogs of pepstatin A, that are nanomolar and selective inhibitors of the protozoal aspartyl protease plasmepsin II.(c) Molteni, M.; Bellucci, M. C.; Bigotti, S.; Mazzini, S.; Volonterio, A.; Zanda, M. Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysis. Org. Biomol. Chem. 2009, 7, 2286– 2296, DOI: 10.1039/b901718f[Crossref], [PubMed], [CAS], Google Scholar160chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFKntrc%253D&md5=d7b00a73b1409503bead497218549024Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysisMolteni, Marco; Bellucci, Maria Cristina; Bigotti, Serena; Mazzini, Stefania; Volonterio, Alessandro; Zanda, MatteoOrganic & Biomolecular Chemistry (2009), 7 (11), 2286-2296CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Ψ[CH(CF3)NH]Gly peptides, a conceptually new class of peptidomimetics having a stereogenic trifluoroethylamine group as a natural peptide-bond surrogate, have been synthesized by aza-Michael stereoselective addn. of α-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. Long range nuclear Overhauser effects, detected via ROESY expts., provided evidence that model Ψ[CH(CF3)NH]Gly-tetrapeptides incorporating a trifluoroethylamine mimic of the dipeptide loop Pro-Gly can be represented by an ensemble of unfolded and folded conformations. The latter are driven by the formation of a hydrogen bond between a carbonyl group and the aminic proton of the trifluoroethylamine unit. MD calcns. indicate a population of conformers which adopt folded β turn structures for all the L-peptides; on the other hand, a D-stereochem. at the Pro residue induces a natural folding towards a β hairpin conformation driven by the formation of a second hydrogen bond, regardless of the stereochem. of the stereogenic peptide bond surrogate.
- 161(a) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Leger, S.; Li, C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741– 4744, DOI: 10.1016/j.bmcl.2005.07.071[Crossref], [PubMed], [CAS], Google Scholar.161ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVanu7%252FE&md5=c2ffc9bde9fbee7bb432d3c2485cfc62Trifluoroethylamines as amide isosteres in inhibitors of cathepsin KBlack, W. Cameron; Bayly, Christopher I.; Davis, Dana E.; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Leger, Serge; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Palmer, James T.; Percival, M. David; Robichaud, Joel; Tsou, Nancy; Zamboni, RobertBioorganic & Medicinal Chemistry Letters (2005), 15 (21), 4741-4744CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The nonbasic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compds. are 10- to 20-fold more potent than the corresponding amide derivs. Compd. (I) is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.(b) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Thérien, M.; Truong, V.-L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985– 1989, DOI: 10.1016/j.bmcl.2005.12.071[Crossref], [PubMed], [CAS], Google Scholar.161bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvVyqs74%253D&md5=e63e471204893774e5a617993ed9be18Identification of a potent and selective non-basic cathepsin K inhibitorLi, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald. B.; Leger, Serge; Masse, Frederic; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Therien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2006), 16 (7), 1985-1989CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of L-873724 (I) as a potent and selective non-basic cathepsin K inhibitor. This compd. showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The vols. of distribution close to unity were consistent with this compd. not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.(c) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.T.; Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923– 928, DOI: 10.1016/j.bmcl.2007.12.047[Crossref], [PubMed], [CAS], Google Scholar.161chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktro%253D&md5=e432a420a3ec99c784117750b9bbeda8The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin KGauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean-Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Leger, Serge; LeRiche, Tammy; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Nicoll-Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Joel; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Therien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2008), 18 (3), 923-928CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclin. species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.(d) Mullard, A. Merck & Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discovery 2016, 15, 669, DOI: 10.1038/nrd.2016.207[Crossref], [CAS], Google Scholar161dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFymtL3M&md5=596d89f78b8396f0193a4ecfaf6b50bdMerck & Co. drops osteoporosis drug odanacatibMullard, AsherNature Reviews Drug Discovery (2016), 15 (10), 669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A discussion of the osteoporosis drug odanacatib.
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- 163Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M.-H.; Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B. T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. Aminomethyl-derived beta secretase (BACE-1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem. 2017, 60, 386– 402, DOI: 10.1021/acs.jmedchem.6b01451
- 164(a) Chen, G.; Ren, H.; Turpoff, A.; Arefolov, A.; Wilde, R.; Takasugi, J.; Khan, A.; Almstead, N.; Gu, Z.; Komatsu, T.; Freund, C.; Breslin, J.; Colacino, J.; Hedrick, J.; Weetall, M.; Karp, G. M. Discovery of N-(4′-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication. Bioorg. Med. Chem. Lett. 2013, 23, 3942– 3946, DOI: 10.1016/j.bmcl.2013.04.050 .(b) Zhang, X.; Zhang, N.; Chen, G.; Turpoff, A.; Ren, H.; Takasugi, J.; Morrill, C.; Zhu, J.; Li, C.; Lennox, W.; Paget, S.; Liu, Y.; Almstead, N.; Njoroge, F. G.; Gu, Z.; Komatsu, T.; Clausen, V.; Espiritu, C.; Graci, J.; Colacino, J.; Lahser, F.; Risher, N.; Weetall, M.; Nomeir, A.; Karp, G. M. Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. Bioorg. Med. Chem. Lett. 2013, 23, 3947– 3953, DOI: 10.1016/j.bmcl.2013.04.049[Crossref], [PubMed], [CAS], Google Scholar.164bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSisrw%253D&md5=c4ea419ba26dea48358a3036caf48abfDiscovery of novel HCV inhibitors: Synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4BZhang, Xiaoyan; Zhang, Nanjing; Chen, Guangming; Turpoff, Anthony; Ren, Hongyu; Takasugi, James; Morrill, Christie; Zhu, Jin; Li, Chunshi; Lennox, William; Paget, Steven; Liu, Yalei; Almstead, Neil; George Njoroge, F.; Gu, Zhengxian; Komatsu, Takashi; Clausen, Valerie; Espiritu, Christine; Graci, Jason; Colacino, Joseph; Lahser, Fred; Risher, Nicole; Weetall, Marla; Nomeir, Amin; Karp, Gary M.Bioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3947-3953CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides I [R1 = CHF2O, c-Pr; R2 = i-Pr, H, CH(CH2F)2, etc.] was prepd. and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compds. with low nanomolar potency against the HCV genotype 1b replicon. Among these, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] was identified as a potent HCV replicon inhibitor (EC50 = 4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] had a good pharmacokinetic profile in rats with an IV half-life of 6 h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compds. These compds. hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.(c) Zhang, N.; Zhang, X.; Zhu, J.; Turpoff, A.; Chen, G.; Morrill, C.; Huang, S.; Lennox, W.; Kakarla, R.; Liu, R.; Li, C.; Ren, H.; Almstead, N.; Venkatraman, S.; Njoroge, F. G.; Gu, Z.; Clausen, V.; Graci, J.; Jung, S. P.; Zheng, Y.; Colacino, J. M.; Lahser, F.; Sheedy, J.; Mollin, A.; Weetall, M.; Nomeir, A.; Karp, G.M. Structure–activity relationship (SAR) optimization of 6-(indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B. J. Med. Chem. 2014, 57, 2121– 2135, DOI: 10.1021/jm401621g
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- 166Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Hiner, R. N.; Dorsey, G. F.; Noe, R. A.; Unwalla, R. J.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; van Arnold, J.; Bickett, D. M.; Moss, M. L.; Tian, G.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Croom, D. K. Structure-activity relationships for inhibition of type 1 and 2 human 5α-reductase and human adrenal 3β-hydroxy-Δ5-steroid dehydrogenase/3-keto-Δ5-steroid isomerase by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent. J. Med. Chem. 1995, 38, 2621– 2627, DOI: 10.1021/jm00014a015
- 167(a) di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A. Novel aromatase and 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol. 1994, 49, 289– 294, DOI: 10.1016/0960-0760(94)90270-4[Crossref], [PubMed], [CAS], Google Scholar.167ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlvFKhs7w%253D&md5=9575b614af25a96aaddeeedfdc695ce1Novel aromatase and 5α-reductase inhibitorsDi Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A.Journal of Steroid Biochemistry and Molecular Biology (1994), 49 (4-6), 289-94CODEN: JSBBEZ; ISSN:0960-0760.Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, resp. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compd. was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compd. was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17β-amidic side chains, three compds., namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5α-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, resp. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compds. were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, resp.(b) Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Ihelè, C.; Nesi, M.; Panzeri, A.; di Salle, E. FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effects. J. Steroid Biochem. Mol. Biol. 1996, 58, 299– 305, DOI: 10.1016/0960-0760(96)00040-4[Crossref], [PubMed], [CAS], Google Scholar.167bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmtFWlurY%253D&md5=d67d010818dd73d38f1b7f4f4ded9465FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effectsGiudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Iehle, C.; Nesi, M.; Panzeri, A.; di Salle, E.Journal of Steroid Biochemistry and Molecular Biology (1996), 58 (3), 299-305CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier)FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compd. causes inhibition of rat and human prostatic enzymes, with IC50 values of 15 an d16 nM, resp., compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isoenzymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isoenzymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult rats, FCE 28260 reduced prostatic DHT concns. 6 h after oral dosing with a potency similar to that of finasteride (65% redn. at 1 mg/kg) but was found to be markedly more potent than the ref. compd. at 24 h (74% redn. in prostate DHT at 10 mg/kg, compared to 26% redn. induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.(c) di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Délos, S.; Martin, P. M. PNU 157706, a novel dual type I and II 5α-reductase inhibitor. J. Steroid Biochem. Mol. Biol. 1998, 64, 179– 186, DOI: 10.1016/S0960-0760(97)00158-1[Crossref], [PubMed], [CAS], Google Scholar.167chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1Siur4%253D&md5=05e5f3843393d77fc18cdb04017eaf76PNU 157706, a novel dual type I and II 5α-reductase inhibitorDi Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Delos, S.; Martin, P. M.Journal of Steroid Biochemistry and Molecular Biology (1998), 64 (3-4), 179-186CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Science Ltd.)PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). Tested on a crude prepn. of human or rat prostatic 5α-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, resp., compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5α-R type I and II isoenzymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isoenzyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting redn. of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, resp.). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate wt. in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate wt., the ED50 values being 0.12 and 1.9 mg/kg/day, resp. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5α-R with a very marked antiprostatic effect in the rat.(d) Basileo, G.; Breda, M.; James, C. A. Determination of PNU-157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection. J. Chromatogr., Biomed. Appl. 1998, 719, 191– 197, DOI: 10.1016/S0378-4347(98)00412-5[Crossref], [PubMed], [CAS], Google Scholar167dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXotFajs7s%253D&md5=badecb35cf011122235d7c7c89aabb12Determination of PNU 157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detectionBasileo, G.; Breda, M.; James, C. A.Journal of Chromatography B: Biomedical Sciences and Applications (1998), 719 (1 + 2), 191-197CODEN: JCBBEP; ISSN:0378-4347. (Elsevier Science B.V.)A HPLC procedure was developed and validated for detg. nanogram per mL concns. of the dual 5a-reductase inhibitor PNU 157706 in rat plasma. The compd. was extd. from plasma with di-Et ether followed by purifn. on a CN cartridge. The chromatog. sepn. was performed on a C18 column with water-acetonitrile-methanol mixt. as eluent. UV detection at 210 nm was used for the quantification of the compd. over the concn. range 5-500 ng/mL plasma. The method has a lower limit of quantification of 5 ng/mL and good precision and accuracy. This method performed well during anal. of several toxicokinetic and pharmacokinetic studies in the rat.
- 168(a) Drury, J. E.; Di Costanzo, L.; Penning, T. M.; Christianson, D. W. Inhibition of human steroid 5α-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex. J. Biol. Chem. 2009, 284, 19786– 19790, DOI: 10.1074/jbc.C109.016931 .(b) Karnsomwan, W.; Rungrotmongkol, T.; De-Eknamkul, W.; Chamni, S. chamni, S. In silico prediction of human steroid 5α-reductase type II. Med. Chem. Res. 2016, 25, 1049– 1056, DOI: 10.1007/s00044-016-1541-y[Crossref], [CAS], Google Scholar168bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVamtL0%253D&md5=5859de732a06e99fb1587ebedb250d34In silico structural prediction of human steroid 5α-reductase type IIKarnsomwan, Wiranpat; Rungrotmongkol, Thanyada; De-Eknamkul, Wanchai; Chamni, SupakarnMedicinal Chemistry Research (2016), 25 (6), 1049-1056CODEN: MCREEB; ISSN:1054-2523. (Springer)Steroid 5α-reductase type II is a membrane-assocd. enzyme in an oxidoreductase family. This enzyme, which is found in male sexual organs, plays the important biol. actions toward steroid metab. Overexpression of 5α-reductase type II has affected the balance between testosterone and dihydrotestosterone, which implicates the androgenic disorders, including prostate cancer, hirsutism, and androgenic alopecia. Lack of single-crystal X-ray structures of 5α-reductase has hindered mechanistic understanding and delayed the discovery and development of an effective inhibitor. Herein, we illustrated a comparative structure of 5α-reductase type II that derived from the homol. modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template. A catalytic pocket and the transmembrane site were identified. The resulting in silico structure was validated via Ramachandran plot and confirmed by docking studies of 30 known 5α-reductase type I and type II inhibitors, including finasteride and dutasteride. The comparative docking study of the derived in silico 5α-reductase type II and 5β-reductase, a reported surrogate enzyme, was conducted. Our homol. model approx. fitted to the membrane-assocd. character and showed the reasonable docking results, which depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.
- 169(a) Howbert, J. J.; Grossman, C. S.; Crowell, T. A.; Rieder, B. J.; Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikins, J.; Poore, G. A. Novel agents effective against solid tumors: the diarylsulfonylureas. Synthesis, activities, and analysis of quantitative structure-activity relationships. J. Med. Chem. 1990, 33, 2393– 2407, DOI: 10.1021/jm00171a013 .(b) Mohamadi, F.; Spees, M. M.; Grindey, G. B. Sulfonylureas: a new class of cancer chemotherapeutic agents. J. Med. Chem. 1992, 35, 3012– 3016, DOI: 10.1021/jm00094a013
- 170(a) Houghton, P. J.; Houghton, J. A. Antitumor diarylsulfonylureas: novel agents with unfulfilled promise. Invest. New Drugs 1996, 14, 271– 280, DOI: 10.1007/BF00194530 .(b) Owa, T.; Nagasu, T. Novel sulphonamide derivatives for the treatment of cancer. Expert Opin. Ther. Pat. 2000, 10, 1725– 1740, DOI: 10.1517/13543776.10.11.1725[Crossref], [CAS], Google Scholar.170bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXnvF2gtb4%253D&md5=b30657724dc8b8ab4a50f733df0aa6f6Novel sulphonamide derivatives for the treatment of cancerOwa, Takashi; Nagasu, TakeshiExpert Opinion on Therapeutic Patents (2000), 10 (11), 1725-1740CODEN: EOTPEG; ISSN:1354-3776. (Ashley Publications Ltd.)A review with 265 refs. is given. The sulfonamides constitute an important class of therapeutic agents in current medicinal science. After the discovery by Gerhard Domagk, of sulphamidochrysoidine (prontosil) as the first antibiotic sulfa-drug an active metabolite of the drug, sulphanilamide, was further derivatized in order to find compds. exhibiting superior antibacterial activity or different pharmacol. effects. Diversification of the sulphanilamide structure led to the serial development of improved antibiotics, insulin-releasing hypoglycemic drugs, carbonic anhydrase- (CA) inhibitory diuretics, anti-hypertensive drugs etc. It is of particular interest that various structurally novel sulfonamide derivs. have recently been reported to show substantial anti-tumor activity in vitro and/or in vivo. Although they have a common chem. motif of an arom./heterocyclic sulfonamide, there are a variety of mechanisms for their anti-tumor action, such as disruption of microtubule assembly, cell cycle arrest in the G1 phase, functional suppression of the transcriptional activator NF-Y, angiogenesis inhibition and carbonic anhydrase inhibition. Furthermore, some of these compds. selected via elaborate preclin. screenings are currently being evaluated in clin. trials. This review summarizes recent patents and related papers which have disclosed novel classes of sulfonamide derivs. for the treatment of cancer.(c) Pasello, G.; Urso, L.; Conte, P.; Favaretto, A. Effects of sulfonylureas on tumor growth: a review of the literature. Oncologist 2013, 18, 1118– 1125, DOI: 10.1634/theoncologist.2013-0177
- 171Forouzesh, B.; Takimoto, C. H.; Goetz, A.; Diab, S.; Hammond, L. A.; Smetzer, L.; Schwartz, G.; Gazak, R.; Callaghan, J. T.; Von Hoff, D. D.; Rowinsky, E. K. A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies. Clin. Cancer Res. 2003, 9, 5540– 5549[PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpsVejtb4%253D&md5=2a6fc397223a4b0a24ee63d73723f1a6A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignanciesForouzesh, Bahram; Takimoto, Chris H.; Goetz, Andrew; Diab, Sami; Hammond, Lisa A.; Smetzer, Leslie; Schwartz, Garry; Gazak, Robert; Callaghan, John T.; Von Hoff, Daniel D.; Rowinsky, Eric K.Clinical Cancer Research (2003), 9 (15), 5540-5549CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 wk every 4-wk schedule. The study also sought to det. the max. tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. The initial starting dose of ILX-295501 was 100 mg/m2, which was equiv. to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m2. Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m2; and a modified continual reassessment model was used for dose assignment to det. the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m2. The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m2, which was detd. to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clin. relevant levels of oxidized Hb (metHb) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concns. (Cmax) achieving 6.02 h, on av., after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent vol. of distribution at steady state (Vss/F), averaging 8.02 ± 14.08 L, and low apparent total body clearance (CLt/F) rate (mean, 0.036 ± 0.116 L/h). The initial drug distribution phase was rapid [harmonic mean half-life (t1/2α), 2.1±7.0 min], whereas the terminal elimination phase was slow (harmonic mean t1/2β, 150.6 ± 80.2 h). The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 wk every 4 wk is 1000 mg/m2/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematol. toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.
- 172(a) Toth, J. E.; Grindey, G. B.; Ehlhardt, W. J.; Ray, J. E.; Boder, G. B.; Bewley, J. R.; Klingerman, K. K.; Gates, S. B.; Rinzel, S. M.; Schultz, R. M.; Weir, L. C.; Worzalla, J. F. Sulfonimidamide analogs of oncolytic sulfonylureas. J. Med. Chem. 1997, 40, 1018– 1025, DOI: 10.1021/jm960673l[ACS Full Text.
], [CAS], Google Scholar172ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhvVKqtLs%253D&md5=8020a75bb8a7b941d754d8a5d6e3aa9cSulfonimidamide Analogs of Oncolytic SulfonylureasToth, John E.; Grindey, Gerald B.; Ehlhardt, William J.; Ray, James E.; Boder, George B.; Bewley, Jesse R.; Klingerman, Kim K.; Gates, Susan B.; Rinzel, Sharon M.; Schultz, Richard M.; Weir, Leonard C.; Worzalla, John F.Journal of Medicinal Chemistry (1997), 40 (6), 1018-1025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for in vitro cytotoxicity against CEM cells, in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and metabolic breakdown to the o-sulfate of p-chloroaniline. The sepd. enantiomers of 1 sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or i.p. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.(b) Chern, J. W.; Leu, Y. L.; Wang, S. S.; Jou, R.; Lee, C. F.; Tsou, P. C.; Hsu, S. C.; Liaw, Y. C.; Lin, H. M. Synthesis and cytotoxic evaluation of substituted sulfonyl-N-hydroxyguanidine derivatives as potential antitumor agents. J. Med. Chem. 1997, 40, 2276– 2286, DOI: 10.1021/jm9607818 - 173(a) Luzina, E. L.; Popov, A. V. Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N′-thiazolyl and N-bis(trifluoromethyl)alkyl-N′-benzothiazolyl ureas. Eur. J. Med. Chem. 2009, 44, 4944– 4953, DOI: 10.1016/j.ejmech.2009.08.007 .(b) Luzina, E. L.; Popov, A. V. Anticancer activity of N-bis(trifluoromethyl)alkyl-N′-(polychlorophenyl) and N′-(1,2,4-triazolyl) ureas. Eur. J. Med. Chem. 2010, 45, 5507– 5512, DOI: 10.1016/j.ejmech.2010.08.057 .(c) Luzina, E. L.; Popov, A. V. Synthesis, evaluation of anticancer activity and COMPARE analysis of N-bis(trifluoromethyl)alkyl-N′-substituted ureas with pharmacophoric moieties. Eur. J. Med. Chem. 2012, 53, 364– 373, DOI: 10.1016/j.ejmech.2012.03.026
- 174Métayer, B.; Compain, G.; Jouvin, K.; Martin-Mingot, A.; Bachmann, C.; Marrot, J.; Evano, G.; Thibaudeau, S. Chemo- and stereo-selective synthesis of fluorinated enamides from ynamides in HF/pyridine: second-generation approach to potent ureas bioisosteres. J. Org. Chem. 2015, 80, 3397– 3410, DOI: 10.1021/jo502699y
- 175(a) Mewshaw, R. E.; Marquis, K. L.; Shi, X.; McGaughey, G.; Stack, G.; Webb, M. B.; Abou-Gharbia, M.; Wasik, T.; Scerni, R.; Spangler, T.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents 4. Exploiting the 2-methyl chroman scaffold. Synthesis and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano [2,3-e]indole and indol-8-one derivatives. Tetrahedron 1998, 54, 7081– 7108, DOI: 10.1016/S0040-4020(98)00349-4 .(b) Mewshaw, R. E.; Verwijs, A.; Shi, X.; McGaughey, G. B.; Nelson, j. A.; Mazandarani, H.; Brennan, J. A.; Marquis, K. L.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. 5. Heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template. Bioorg. Med. Chem. Lett. 1998, 8, 2675– 2680, DOI: 10.1016/S0960-894X(98)00474-0[Crossref], [PubMed], [CAS], Google Scholar.175bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntV2kt7s%253D&md5=e57316b9156bfe85ea046b9dd7b4eec5New generation dopaminergic agents. 5. heterocyclic bioisosteres that exploit the 3-OH-N'-phenylpiperazine dopaminergic templateMewshaw, Richard E.; Verwijs, Antoine; Shi, Xiaojie; Mcgaughey, Georgia B.; Nelson, James A.; Mazandarani, Hossein; Brennan, Julie A.; Marquis, Karen L.; Coupet, Joseph; Andree, Terrance H.Bioorganic & Medicinal Chemistry Letters (1998), 8 (19), 2675-2680CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis of several bioisosteric analogs based on the 3-OH-N'-phenylpiperazine dopamine D2 agonist template is described. The indolone (I) and 2-CF3-benzimidazole (II) were obsd. to have excellent affinity for the D2 receptor. Several D4 selective compds. were also identified. Mol. modeling studies and a putative bioactive conformation are discussed.(c) Mewshaw, R. E.; Nelson, J. A.; Shah, U. S.; Shi, X.; Mazandarani, H.; Coupet, J.; Marquis, K.; Brennan, J. A.; Andree, T. H. New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template. Bioorg. Med. Chem. Lett. 1999, 9, 2593– 2598, DOI: 10.1016/S0960-894X(99)00434-5 .(d) Mewshaw, R. E.; Zhao, R.; Shi, X.; Marquis, K.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. Part 8: heterocyclic bioisosteres that exploit the 7-OH-2-(aminomethyl)chroman D2 template. Bioorg. Med. Chem. Lett. 2002, 12, 271– 274, DOI: 10.1016/S0960-894X(01)00778-8
- 176Banks, J. W.; Batsanov, A. S.; Howard, J. A. K.; O’Hagan, D.; Rzepa, H. S.; Martin-Santamaria, S. The preferred conformation of α-fluoroamides. J. Chem. Soc., Perkin Trans. 2 1999, 2409– 2411, DOI: 10.1039/a907452j[Crossref], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmvFyku70%253D&md5=2f07b92ce6ca5799dbb3017f2a67263fThe preferred conformation of α-fluoroamidesBanks, John W.; Batsanov, Andrei S.; Howard, Judith A. K.; O'Hagan, David; Rzepa, Henry S.; Martin-Santamaria, SonsolesJournal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1999), (11), 2409-2411CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)X-Ray structures of two α-fluoroamide derivs. show the O:C-C-F moiety tending towards a trans planar conformation, for which ab initio calcns. suggest a deep (up to 8 kcal mol-1) potential min.
- 177Olivato, P. R.; Guerrero, S. A.; Yreijo, M. H.; Rittner, R.; Tormena, C. F. Conformational and electronic interaction studies of 2-fluoro-substituted N,N-dimethylamides. J. Mol. Struct. 2002, 607, 87– 99, DOI: 10.1016/S0022-2860(01)00761-X
- 178Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. The C-F bond as a tool in the conformational control of amides. J. Fluorine Chem. 2003, 119, 9– 13, DOI: 10.1016/S0022-1139(02)00243-9[Crossref], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsVektLs%253D&md5=1654f99734ae8bc262c6409d13382ff5The C-F bond as a tool in the conformational control of amidesBriggs, Caroline R. S.; O'Hagan, David; Howard, Judith A. K.; Yufit, Dmitrii S.Journal of Fluorine Chemistry (2003), 119 (1), 9-13CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science B.V.)The conformation of 2-fluoro-N-(2-fluoroethyl)-propionamide 4 in the solid state indicates the influence of both a β-F-amide gauche effect and an α-fluoroamide effect. The structure reveals the influence of two recently obsd. stereoelectronic effects assoc. with the C-F bond, which resulted in the successful prediction of the solid state conformation of amide 4. A gauche relation (-69.9°) was obsd. for atoms N(1)-C(4)-C(5)-F and a syn planar (2.0°) relation was obsd. for N(1)-C(3)-C(2)-F. The paper demonstrates the predictive power of using the C-F bond as a tool in influencing the conformation of amides and peptides.
- 179Winkler, M.; Moraux, T.; Khairy, H. A.; Scott, R. H.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and vanilloid receptor (TRPV1) activity of the enantiomers of α-fluorinated capsaicin. ChemBioChem 2009, 10, 823– 828, DOI: 10.1002/cbic.200800709
- 180(a) Jones, C. R.; Baruah, P. K.; Thompson, A. L.; Scheiner, S.; Smith, M. D. Can. a C–H···O interaction be a determinant of conformation?. J. Am. Chem. Soc. 2012, 134, 12064– 12071, DOI: 10.1021/ja301318a .(b) Driver, R. W.; Claridge, T. D. W.; Scheiner, S.; Smith, M. D. Torsional and electronic factors control the C–H···O interaction. Chem. - Eur. J. 2016, 22, 16513– 16521, DOI: 10.1002/chem.201602905[Crossref], [PubMed], [CAS], Google Scholar.180bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1ejtrnO&md5=5d9c737d8b5a6e4604897d094fc02d18Torsional and Electronic Factors Control the C-H...O InteractionDriver, Russell W.; Claridge, Timothy D. W.; Scheiner, Steve; Smith, Martin D.Chemistry - A European Journal (2016), 22 (46), 16513-16521CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The precise role of nonconventional hydrogen bonds such as the C-H...O interaction in influencing the conformation of small mols. remains unresolved. Here the authors survey β-turn mimetics using x-ray crystallog. and NMR spectroscopy in conjunction with quantum calcn., and conclude that favorable torsional and electronic effects are important for the population of states with conformationally influential C-H...O interactions. Results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions to focus on the contribution of a single one. Within a small mol. that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chem. shift data are extremely challenging to rationalize.(c) Koeller, S.; Thomas, C.; Peruch, F.; Deffieux, A.; Massip, S.; Léger, J.-M.; Desvergne, J.-P.; Milet, A.; Bibal, B. α-Halogenoacetanilides as hydrogen-bonding organocatalysts that activate carbonyl bonds: fluorine versus chlorine and bromine. Chem. - Eur. J. 2014, 20, 2849– 2859, DOI: 10.1002/chem.201303662[Crossref], [PubMed], [CAS], Google Scholar.180chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFSnsrk%253D&md5=1a36d371373fec506a463a59036f103aα-Halogenoacetanilides as Hydrogen-Bonding Organocatalysts that Activate Carbonyl Bonds: Fluorine versus Chlorine and BromineKoeller, Sylvain; Thomas, Coralie; Peruch, Frederic; Deffieux, Alain; Massip, Stephane; Leger, Jean-Michel; Desvergne, Jean-Pierre; Milet, Anne; Bibal, BrigitteChemistry - A European Journal (2014), 20 (10), 2849-2859CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)α-Halogenoacetanilides (X = F, Cl, Br) with substituents on the Ph ring were examd. as H-bonding organocatalysts designed for the double activation of C=O bonds through NH and CH donor groups. Depending on the halide substituents, the double H-bond involved a nonconventional C···H···O interaction with either a H-CXn (n= 1-2, X = Cl, Br) or a H-CAr bond (X = F), as shown in the solid-state crystal structures and by mol. modeling. In addn., the catalytic properties of α-haloacetanilides were evaluated in the ring-opening polymn. of lactide, in the presence of a tertiary amine as cocatalyst. The α-dichloro- and α-dibromoacetanilides contg. electron-deficient arom. groups afforded the most attractive double H-bonding properties towards C=O bonds, with a N-H···O···H···CX2 interaction.(d) Jaun, B.; Seebach, D.; Mathad, R. I. Note: Helix or no helix of β-peptides containing β3hAla(αF) residues?. Helv. Chim. Acta 2011, 94, 355– 361, DOI: 10.1002/hlca.201100023 .(e) Chekhlov, A. N.; Aksinenko, A. Yu.; Pushin, A. N.; Sokolov, V. B. An unusually strong intramolecular C-H•••N hydrogen bond in 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine. Russ. Chem. Bull. 1995, 44, 1531– 1532, DOI: 10.1007/BF00714447 .(f) Chekhlov, A. N. Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine with an unusually short intramolecular C-H•••N hydrogen bond. Kristallografiya 1995, 842– 847[CAS], Google Scholar.180fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXos1OnsbY%253D&md5=2dfa2d9e428ef57caaa9565fd2b028b8Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-(α-hydroperfluoroisobutyryl)imino-1,3-thiazolidine with an unusually short intramolecular C-H···N hydrogen bondChekhlov, A. N.Kristallografiya (1995), 40 (5), 842-7CODEN: KRISAJ; ISSN:0023-4761. (MAIK Nauka)The title compd. is monoclinic, space group P21/n, with a 9.203(1), b 10.349(1), c 17.299(2) Å, and β 95.74(1)°; Z = 4, dc = 1.857; R = 0.059 for 2075 reflections. At. coordinates are given. The 5-membered thiazolidine ring has half-chair conformation. This mol. has an unusually short H bond C-H...N with H...N distance 2.00(3) Å. The mol. also has a significantly shortened contact S...O 2.652(2) Å, with nonvalent interaction between S and O atoms. In the crystal structure, the mols. are connected in centrosym. dimer pairs with intermol. H bonds of C-H...O type with H...O distance of 2.38(3) Å.(g) Brewitz, L.; Arteaga Arteaga, F.; Yin, L.; Alagiri, K.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric Mannich-type reaction of α- and β-fluorinated amides. J. Am. Chem. Soc. 2015, 137, 15929– 15939, DOI: 10.1021/jacs.5b11064[ACS Full Text.
], [CAS], Google Scholar180ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVanurfN&md5=47c9b3a6c40395ae00ea0e6e6e803f67Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated AmidesBrewitz, Lennart; Arteaga, Fernando Arteaga; Yin, Liang; Alagiri, Kaliyamoorthy; Kumagai, Naoya; Shibasaki, MasakatsuJournal of the American Chemical Society (2015), 137 (50), 15929-15939CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amts. of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivs. for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-contg. small mols., α- and β-fluorinated carbonyl compds. have been neglected in direct enolization chem. because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Bronsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chem.(h) Brewitz, L.; Noda, H.; Kumagai, N.; Shibasaki, M. Structural and computational investigation of intramolecular N•••H interactions in α- and β-fluorinated 7-azaindoline amides. Eur. J. Org. Chem. 2017, DOI: 10.1002/ejoc.201701083 - 181Jones, C. R.; Dan Pantos, G. D.; Morrison, A. J.; Smith, M. D. Plagiarizing proteins: enhancing efficiency in asymmetric hydrogen-bonding catalysis through positive cooperativity. Angew. Chem., Int. Ed. 2009, 48, 7391– 7394, DOI: 10.1002/anie.200903063[Crossref], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFGrs7%252FI&md5=719944fad5c7ebfca0ee752d774f3e32Plagiarizing Proteins: Enhancing Efficiency in Asymmetric Hydrogen-Bonding Catalysis through Positive CooperativityJones, Christopher R.; Dan Pantos, G.; Morrison, Angus J.; Smith, Martin D.Angewandte Chemie, International Edition (2009), 48 (40), 7391-7394, S7391/1-S7391/127CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A hairpin turn intramol. H-bonded thiourea-urea catalyst was proficient in the highly enantioselective Mukaiyama-Mannich reaction of arom. BOC-aldimines with silyl ketene acetal nucleophile, providing β-aryl β-amino acids in 97 to >99% ee. Deletion of the urea H-bond donor group revealed that the effect of conformational ordering on the asym. induction is significant but relatively small. The intramol. H-bonded catalyst out-competed the urea-deleted catalyst in a competition reaction, suggesting tighter ligand-receptor binding in the transition state and tighter noncovalent interactions in the former case, and also exhibited higher anion-binding ability - consistent with cooperative ligand binding.
- 182Unione, L.; Alcalá, M.; Echeverria, B.; Serna, S.; Ardá, A.; Franconetti, A.; Cañada, F. J.; Diercks, T.; Reichardt, N.; Jiménez-Barbero, J. Fluoroacetamide moieties as NMR spectroscopy probes for the molecular recognition of GlcNAc-containing sugars: modulation of the CH−π stacking interactions by different fluorination patterns. Chem. - Eur. J. 2017, 23, 3957– 3965, DOI: 10.1002/chem.201605573[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtlymsrY%253D&md5=91246ebe88bc77a9219ffb10695eae1dFluoroacetamide Moieties as NMR Spectroscopy Probes for the Molecular Recognition of GlcNAc-Containing Sugars: Modulation of the CH-π Stacking Interactions by Different Fluorination PatternsUnione, Luca; Alcala, Maria; Echeverria, Begona; Serna, Sonia; Arda, Ana; Franconetti, Antonio; Canada, F. Javier; Diercks, Tammo; Reichardt, Niels; Jimenez-Barbero, JesusChemistry - A European Journal (2017), 23 (16), 3957-3965CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)We herein propose the use of fluoroacetamide and difluoroacetamide moieties as sensitive tags for the detection of sugar-protein interactions by simple 1H and/or 19F NMR spectroscopy methods. In this process, we have chosen the binding of N,N'-diacetyl chitobiose, a ubiquitous disaccharide fragment in glycoproteins, by wheat-germ agglutinin (WGA), a model lectin. By using satn.-transfer difference (STD)-NMR spectroscopy, we exptl. demonstrate that, under soln. conditions, the mol. that contained the CHF2CONH- moiety is the stronger arom. binder, followed by the analog with the CH2FCONH- group and the natural mol. (with the CH3CONH- fragment). In contrast, the mol. with the CF3CONH- isoster displayed the weakest intermol. interaction (one order of magnitude weaker). Because sugar-arom. CH-π interactions are at the origin of these observations, these results further contribute to the characterization and exploration of these forces and offer an opportunity to use them to unravel complex recognition processes.
- 183(a) Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.; Adam, G.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J. Med. Chem. 1994, 37, 3231– 3239, DOI: 10.1021/jm00046a006[ACS Full Text.
], [CAS], Google Scholar183ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmsFGgur4%253D&md5=e49a9e7136e045b8ba131d3281fe7082Synthesis and Structure-Activity Relationships of Novel Naphthalenic and Bioisosteric Related Amidic Derivatives as Melatonin Receptor LigandsDepreux, Patrick; Lesieur, Daniel; Mansour, Hamid Ait; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; et al.Journal of Medicinal Chemistry (1994), 37 (20), 3231-9CODEN: JMCMAR; ISSN:0022-2623.A series of N-naphthylethyl amide derivs. were synthesized and evaluated as melatonin receptor ligands. The affinity of each compd. for the melatonin receptor was detd. by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent on the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analog was a poor ligand. N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, a selective ligand of the melatonin receptor and an agonist deriv., has been selected for clin. development.(b) Leclerc, V.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola-Lemaître, B.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. 1998, 6, 1875– 1887, DOI: 10.1016/S0968-0896(98)00147-3[Crossref], [PubMed], [CAS], Google Scholar.183bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntlOhtbs%253D&md5=6ed68fd9dbf928caa550601c70cb3200Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligandsLeclerc, Veronique; Fourmaintraux, Eric; Depreux, Patrick; Lesieur, Daniel; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola-Lemaitre, Beatrice; Andrieux, JeanBioorganic & Medicinal Chemistry (1998), 6 (10), 1875-1887CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogs of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n-Pr urea deriv. is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This mol., a Pr deriv., or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclin. development.(c) Ettaoussi, M.; Sabaouni, A.; Rami, M.; Boutin, J. A.; Delagrange, P.; Renard, P.; Spedding, M.; Caignard, D.-H.; Berthelot, P.; Yous, S. Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). Eur. J. Med. Chem. 2012, 49, 310– 323, DOI: 10.1016/j.ejmech.2012.01.027 .(d) Zlotos, D. P.; Riad, N. M.; Osman, M. B.; Dodda, B. R.; Witt-Enderby, P. A. Novel difluoroacetamide analogues of agomelatine and melatonin: probing the melatonin receptors for MT1 selectivity. MedChemComm 2015, 6, 1340– 1344, DOI: 10.1039/C5MD00190K - 184Qiu, X.-L.; Xu, X.-H.; Qing, F.-L. Recent advances in the synthesis of fluorinated nucleosides. Tetrahedron 2010, 66, 789– 843, DOI: 10.1016/j.tet.2009.11.001
- 185Noble, S.; Goa, K. L. Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 1997, 54, 447– 472, DOI: 10.2165/00003495-199754030-00009[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvFelt7c%253D&md5=2479ca53d998ad70275a54db2b212169Gemcitabine. A review of its pharmacology and clinical potential in non-small-cell lung cancer and pancreatic cancerNoble, Stuart; Goa, Karen L.Drugs (1997), 54 (3), 447-472CODEN: DRUGAY; ISSN:0012-6667. (Adis)A review with 119 refs. Gemcitabine is a deoxycytidine analog which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy. Gemcitabine monotherapy produced an objective tumor response in 18-26% of patients with advanced non-small-cell lung cancer (NSCLC) and appears to have efficacy similar to that of cisplatin plus etoposide. Objective response rates ranging 26-54% were recorded when gemcitabine was combined with cisplatin, and 1-yr survival duration after such treatment ranged 35-61%. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clin. trials. Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addn., direct costs assocd. with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options. The combination of gemcitabine plus cisplatin was assocd. with a lower cost-per-tumor response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness anal. In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clin. status. It also showed modest antitumor and palliative efficacy in patients refractory to fluorouracil. Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerability profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study. Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity assocd. with many other chemotherapy regimens. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and palliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognized.
- 186Hui, C. K.; Lau, G.K. K. Clevudine for the treatment of chronic hepatitis B virus infection. Expert Opin. Invest. Drugs 2005, 14, 1277– 1284, DOI: 10.1517/13543784.14.10.1277
- 187(a) Sofia, M. J.; Bao, S.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Micolochick Steur, H. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis c virus. J. Med. Chem. 2010, 53, 7202– 7218, DOI: 10.1021/jm100863x .(b) Appleby, T. C.; Perry, J. K.; Murakami, E.; Barauskas, O.; Feng, J.; Cho, A.; Fox, D., III; Wetmore, D. R.; McGrath, M. E.; Ray, A. S.; Sofia, M. J.; Swaminathan, S.; Edwards, T. E. Structural basis for RNA replication by the hepatitis C virus polymerase. Science 2015, 347, 771– 775, DOI: 10.1126/science.1259210[Crossref], [PubMed], [CAS], Google Scholar187bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlKktrk%253D&md5=aeebcacedf36a44ae80c972100c80c24Structural basis for RNA replication by the hepatitis C virus polymeraseAppleby, Todd C.; Perry, Jason K.; Murakami, Eisuke; Barauskas, Ona; Feng, Joy; Cho, Aesop; Fox, David, III; Wetmore, Diana R.; McGrath, Mary E.; Ray, Adrian S.; Sofia, Michael J.; Swaminathan, S.; Edwards, Thomas E.Science (Washington, DC, United States) (2015), 347 (6223), 771-775CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Nucleotide analog inhibitors have shown clin. success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by detg. crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our anal. revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A β loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clin. active metabolite formed by sofosbuvir, to elucidate key mol. interactions in the active site.
- 188Van Roey, P.; Salerno, J. M.; Chu, C.-K.; Schinazi, R. F. Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 3929– 3933, DOI: 10.1073/pnas.86.11.3929
- 189Gore, K. R.; Harikrishna, S.; Pradeepkumar, P. I. Influence of 2′-fluoro versus 2′-O-methyl substituent on the sugar puckering of 4′-C-aminomethyluridine. J. Org. Chem. 2013, 78, 9956– 9962, DOI: 10.1021/jo4012333
- 190Zeng, D.; Zhang, R.; Nie, Q.; Cao, L.; Shang, L.; Yin, Z. Discovery of 2′-α-C-methyl-2′-β-C-fluorouridine phosphoramidate prodrugs as inhibitors of hepatitis C virus. ACS Med. Chem. Lett. 2016, 7, 1197– 1201, DOI: 10.1021/acsmedchemlett.6b00270
- 191Pallan, P. S.; Prakash, T. P.; de Leon, A. R.; Egli, M. Limits of RNA 2′-OH mimicry by fluorine: crystal structure of bacillus halodurans RNase H bound to a 2′-FRNA:DNA hybrid. Biochemistry 2016, 55, 5321– 5325, DOI: 10.1021/acs.biochem.6b00849[ACS Full Text
], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyhsL%252FN&md5=2bc94b04210f229dbee2b2f60bed9155Limits of RNA 2'-OH mimicry by fluorine: Crystal structure of Bacillus halodurans RNase H bound to a 2'-FRNA:DNA hybridPallan, Pradeep S.; Prakash, Thazha P.; de Leon, Arnie R.; Egli, MartinBiochemistry (2016), 55 (38), 5321-5325CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)RNase H1 cleaves the RNA strand of RNA:DNA hybrids. Replacement of RNA 2'-OH groups by F (FRNA) is commonly used to stabilize aptamers and siRNAs. However, FRNA:DNA hybrids fail to elicit RNase H1 activity. The underlying reasons are unclear, as 2'-OH groups are not directly involved in cleavage. Here, the authors detd. the crystal structure of Bacillus halodurans RNase H1 bound to a FRNA:DNA hybrid. The structure pointed to dynamic (slippage of the FRNA:DNA hybrid relative to the enzyme), geometric (different curvatures of FRNA:DNA and RNA:DNA hybrids), and electronic reasons (Mg2+ absent from the active site of the FRNA:DNA complex) for the loss of RNase H1 activity. - 192(a) Hinderaker, M. P.; Raines, R. T. An electronic effect on protein structure. Protein Sci. 2003, 12, 1188– 1194, DOI: 10.1110/ps.0241903[Crossref], [PubMed], [CAS], Google Scholar.192ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktV2ls78%253D&md5=221803b3d17053ea4f4804ccf372e55aAn electronic effect on protein structureHinderaker, Matthew P.; Raines, Ronald T.Protein Science (2003), 12 (6), 1188-1194CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)The well-known preference of the peptide bond for the trans conformation has been attributed to steric effects. Here, we show that a proline residue with an N-formyl group (Hi-1-C'i-1=Oi-1), in which Hi-1 presents less steric hindrance than does Oi-1, likewise prefers a trans conformation. Thus, the preference of the peptide bond for the trans conformation cannot be explained by steric effects alone. Rather, an n → π* interaction between the oxygen of the peptide bond (Oi-1), and the subsequent carbonyl carbon in the polypeptide chain (C'i) also contributes to this preference. The Oi-1 and C'i distance and Oi-1···C'i=Oi angle are esp. favorable for such an n → π* interaction in a polyproline II helix. We propose that this electronic effect provides substantial stabilization to this and other elements of protein structure.(b) Horng, J.-C.; Raines, R. T. Stereoelectronic effects on polyproline conformation. Protein Sci. 2006, 15, 74– 83, DOI: 10.1110/ps.051779806[Crossref], [PubMed], [CAS], Google Scholar.192bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktlSrtw%253D%253D&md5=07024cb52046bd729b1e9da61eb9bbafStereoelectronic effects on polyproline conformationHorng, Jia-Cherng; Raines, Ronald T.Protein Science (2006), 15 (1), 74-83CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)The polyproline type II (PPII) helix is a prevalent conformation in both folded and unfolded proteins, and is known to play important roles in a wide variety of biol. processes. Polyproline itself can also form a type I (PPI) helix, which has a disparate conformation. Here, we use derivs. of polyproline, (Pro)10, (Hyp)10, (Flp)10, and (flp)10, where Hyp is (2S,4R)-4-hydroxyproline, Flp is (2S,4R)-4-fluoroproline, and flp is (2S,4S)-4-fluoroproline, to probe for a stereoelectronic effect on the conformation of polyproline. CD spectral analyses show that 4R electron-withdrawing substituents stabilize a PPII helix relative to a PPI helix, even in a solvent that favors the PPI conformation, such as n-propanol. The stereochem. at C4 ordains the relative stability of PPI and PPII helixes, as (flp)10 forms a mixt. of PPI and PPII helixes in water and a PPI helix in n-propanol. The conformational preferences of (Pro)10 are intermediate between those of (Hyp)10/(Flp)10 and (flp)10. Interestingly, PPI helixes of (flp)10 exhibit cold denaturation in n-propanol with a value of Ts near 70°. Together, these data show that stereoelectronic effects can have a substantial impact on polyproline conformation and provide a rational means to stabilize a PPI or PPII helix.(c) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. Conformational stability of collagen relies on a stereoelectronic effect. J. Am. Chem. Soc. 2001, 123, 777– 778, DOI: 10.1021/ja005542v[ACS Full Text
], [CAS], Google Scholar192chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1Kr&md5=e098730171588bbb036f712d1b424675Conformational Stability of Collagen Relies on a Stereoelectronic EffectBretscher, Lynn E.; Jenkins, Cara L.; Taylor, Kimberly M.; DeRider, Michele L.; Raines, Ronald T.Journal of the American Chemical Society (2001), 123 (4), 777-778CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Here, we demonstrate for the first time that a stereoelectronic effect is crit. for the conformational stability of a protein. - 193Bacqué, E. Influence of fluorination at position 16 of antibacterial pristinamycins II. Chimia 2004, 58, 128– 132, DOI: 10.2533/000942904777678109
- 194Erickson, J.; McLoughlin, J. I. Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem. 1995, 60, 1626– 1631, DOI: 10.1021/jo00111a021[ACS Full Text
], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktleksrY%253D&md5=efa305f99bfa66ac92aa3b72942289b4Hydrogen Bond Donor Properties of the Difluoromethyl GroupErickson, Jon A.; McLoughlin, Jim I.Journal of Organic Chemistry (1995), 60 (6), 1626-31CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A theor. and exptl. study of the existence and the properties of the difluoromethyl group acting as a hydrogen bond donor has been carried out. An intramol. CF2H...O:C interaction was examd. using semiempirical MO calcns. of both a non-hydrogen-bonded and hydrogen-bonded conformation of a CF2H-substituted pyrazolecarboxamide fungicide. Results revealed a short H...O contact, a significant energy stabilization, and a lowering in the IR spectrum of 22 cm-1. The exptl. IR spectrum of this mol. gave two carbonyl stretching frequencies, one lower by 18 cm-1, very similar to the calcd. no. Low-temp. NMR results are also consistent with a geometry having the possibility of an intramol. CF2H...O:C hydrogen bond. The hydrogen bond in this system may be related to the enhanced biol. activity of the CF2H compd. over its CF3 counterpart. In addn., ab initio MO methods were employed to examine inter- and intramol. hydrogen-bonding models of the difluoromethyl group. The results showed that the CF2H...O:C interaction has a binding energy of ∼1.0 kcal mol-1 and a H...O distance of ∼2.4 Å. - 195(a) Walter, H.; Tobler, H.; Gribkov, D.; Corsi, D. Sedaxane, isopyrazam and solatenol: novel broad-spectrum fungicides inhibiting succinate dehydrogenase (SDH) - synthesis challenges and biological aspects. Chimia 2015, 69, 425– 434, DOI: 10.2533/chimia.2015.425 .(b) Jeschke, P. Progress of modern agricultural chemistry and future prospects. Pest Manage. Sci. 2016, 72, 433– 455, DOI: 10.1002/ps.4190[Crossref], [PubMed], [CAS], Google Scholar195bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitV2msLjF&md5=a46dd1c0017a749afdac4b8a29ebb3c7Progress of modern agricultural chemistry and future prospectsJeschke, PeterPest Management Science (2016), 72 (3), 433-455CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)Agriculture is facing an enormous challenge: it must ensure that enough high-quality food is available to meet the needs of a continually growing population. Current and future agronomic prodn. of food, feed, fuel and fiber requires innovative solns. for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands, renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chem. has to support farmers to manage these tasks. Today, the so-called 'side effects' of agrochems. regarding yield and quality are gaining more importance. Agrochem. companies with a strong research and development focus will have the opportunity to shape the future of agriculture by delivering innovative integrated solns. This review gives a comprehensive overview of the innovative products launched over the past 10 years and describes the progress of modern agricultural chem. and its future prospects. © 2015 Society of Chem. Industry.
- 196Goldberg, K.; Groombridge, S.; Hudson, J.; Leach, A. G.; MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.; Sweeney, J. Oxadiazole isomers: all bioisosteres are not created equal. MedChemComm 2012, 3, 600– 604, DOI: 10.1039/c2md20054f[Crossref], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFart7o%253D&md5=83a31c533e43296d8f681d4063f731b8Oxadiazole isomers: all bioisosteres are not created equalGoldberg, Kristin; Groombridge, Sam; Hudson, Julian; Leach, Andrew G.; MacFaul, Philip A.; Pickup, Adrian; Poultney, Ruth; Scott, James S.; Svensson, Per H.; Sweeney, JosephMedChemComm (2012), 3 (5), 600-604CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compds. were evaluated and found to have significant differences in their various phys. and pharmaceutical properties. Exptl. and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.
- 197(a) Narjes, F.; Koehler, K. F.; Koch, U.; Gerlach, B.; Colarusso, S.; Steinkuhler, C.; Brunetti, M.; Altamura, S.; De Francesco, R.; Matassa, V. G. A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease. Bioorg. Med. Chem. Lett. 2002, 12, 701– 704, DOI: 10.1016/S0960-894X(01)00842-3[Crossref], [PubMed], [CAS], Google Scholar.197ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtFKqur8%253D&md5=3797b78c5827e4db42a7170844d0c0cbA designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 proteaseNarjes, Frank; Koehler, Konrad F.; Koch, Uwe; Gerlach, Benjamin; Colarusso, Stefania; Steinkuhler, Christian; Brunetti, Mirko; Altamura, Sergio; De Francesco, Raffaele; Matassa, Victor G.Bioorganic & Medicinal Chemistry Letters (2002), 12 (4), 701-704CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The difluoromethyl group was designed by computational chem. methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor AcAspGlu-NHCH(CHPH2)CO-Glu-NHCH(CH2C6H11)CONHCH(CH2CHF2)R (I, R = CHO) Ki 30 nM and reversible covalent inhibitors (I, R = CO2H) Ki 0.5 nM; and (I, R = COCO2H) Ki* 10 pM.(b) Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.; Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V. G.; Sollazzo, M. J. Inhibition of the hepatitis C virus NS3/4A protease: the crystal structures of two protease-inhibitor complexes. J. Biol. Chem. 2000, 275, 7152– 7157, DOI: 10.1074/jbc.275.10.7152 .(c) Ontoria, J. M.; Di Marco, S.; Conte, I.; Di Francesco, M. E.; Gardelli, C.; Koch, U.; Matassa, V. G.; Poma, M.; Steinkühler, C.; Volpari, C.; Harper, S. The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease. J. Med. Chem. 2004, 47, 6443– 6446, DOI: 10.1021/jm049435d
- 198(a) Desiraju, G. R. The C-H···O hydrogen bond: structural implications and supramolecular design. Acc. Chem. Res. 1996, 29, 441– 449, DOI: 10.1021/ar950135n[ACS Full Text.
], [CAS], Google Scholar198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XltVKgsbY%253D&md5=549f714126277225e227416794716df5The C-H···O Hydrogen Bond: Structural Implications and Supramolecular DesignDesiraju, Gautam R.Accounts of Chemical Research (1996), 29 (9), 441-449CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review with 64 refs.(b) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem. 2017, 60, 797– 804, DOI: 10.1021/acs.jmedchem.6b01691[ACS Full Text.
], [CAS], Google Scholar198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis12jtw%253D%253D&md5=36159f57b99aa812693f32ff38e88406Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" ConceptZafrani, Yossi; Yeffet, Dina; Sod-Moriah, Gali; Berliner, Anat; Amir, Dafna; Marciano, Daniele; Gershonov, Eytan; Saphier, SigalJournal of Medicinal Chemistry (2017), 60 (2), 797-804CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is a growing interest in org. compds. contg. the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepd. and their drug-like properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were detd. using Abraham's solute 1H NMR anal. The difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the exptl. Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ consts. These results may aid in the rational design of drugs contg. the difluoromethyl moiety.(c) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. CF2H, a hydrogen bond donor. J. Am. Chem. Soc. 2017, 139, 9325– 9332, DOI: 10.1021/jacs.7b04457[ACS Full Text
], [CAS], Google Scholar198chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Kgtbo%253D&md5=f2345db11c3f695f3056c3c8cdad746cCF2H, a Hydrogen Bond DonorSessler, Chanan D.; Rahm, Martin; Becker, Sabine; Goldberg, Jacob M.; Wang, Fang; Lippard, Stephen J.Journal of the American Chemical Society (2017), 139 (27), 9325-9332CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The CF2H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed ty crystallog., spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CF2H groups and the important roles of CF2-H···O hydrogen bonds in influencing intermol. interactions and conformational preferences. Exptl. evidence, corroborated by theory, reveals the distinctive nature of CF2H hydrogen bonding interactions relative to their normal OH hydrogen bonding counterparts. - 199Zheng, Z. B.; D’Andrea, S. V.; Sun, L.-Q.; Wang, A. X.; Chen, Y.; Bowsher, M.; Hiebert, S.; Friborg, J.; Falk, P.; Hernandez, D.; Yu, F.; Sheaffer, A. K.; Zhai, G.; Knipe, J. O.; Mosure, K.; Rajamani, R.; Ng, A.; Gao, Q.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Sulfonamide inhibitors of hepatitis C virus NS3 protease bearing a novel P1 cyclopropyl difluoromethyl moiety. ACS Med. Chem. Lett., 2018, DOI : DOI: 10.1021/acsmedchemlett.7b00503
- 200Lin, C.-W.; Dutta, S.; Asatryan, A.; Chiu, Y.-L.; Wang, H.; Clifton, J., II; Campbell, A.; Liu, W. Pharmacokinetics, safety, and tolerability of single and multiple doses of ABT-493: a first-in-human study. J. Pharm. Sci. 2017, 106, 645– 651, DOI: 10.1016/j.xphs.2016.10.007
- 201Rodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E. GS-9857 in patients with chronic hepatitis C virus genotype 1–4 infection: a randomized, double-blind, dose-ranging phase 1 study. J. Viral Hepatitis 2016, 23, 614– 622, DOI: 10.1111/jvh.12527[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFOkurbK&md5=257769b545cb4289b8f9fc5298454f91GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 studyRodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E.Journal of Viral Hepatitis (2016), 23 (8), 614-622CODEN: JVHEER; ISSN:1365-2893. (John Wiley & Sons Ltd.)Summary : GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-assocd. variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 lab. abnormalities were obsd. in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alk. phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median max. redns. in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was assocd. with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
- 202(a) Xu, Y.; Prestwich, G. D. Concise synthesis of acyl migration-blocked 1,1-difluorinated analogues of lysophosphatidic acid. J. Org. Chem. 2002, 67, 7158– 7161, DOI: 10.1021/jo0203037[ACS Full Text.
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We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from D-mannitol 1,2:5,6-bis-acetonide to give two 1,1-difluorodeoxy analogs of (2R)-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the labile sn-2 LPA species. The 19F NMR of diastereotopic fluorines of the difluoromethyl group shows an unexpected solvent dependence.(b) Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich, G. D. Synthesis of difluoromethyl substituted lysophosphatidic acid analogues. Tetrahedron 2004, 60, 43– 49, DOI: 10.1016/j.tet.2003.11.001[Crossref], [CAS], Google Scholar202bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpslOjt7c%253D&md5=89be69d1a022068ca6daa5bd6cb9b4d1Synthesis of difluoromethyl substituted lysophosphatidic acid analoguesXu, Yong; Qian, Lian; Pontsler, Aaron V.; McIntyre, Thomas M.; Prestwich, Glenn D.Tetrahedron (2004), 60 (1), 43-49CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biol. that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogs of 2-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogs are fully active as natural LPA. - 203(a) Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Suresh, M. R.; Knaus, E. E. Synthesis of celecoxib analogues possessing an N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. J. Med. Chem. 2009, 52, 1525– 1529, DOI: 10.1021/jm8015188 .(b) Yu, G.; Praveen Rao, P. N.; Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Velázquez, C. A.; Suresh, M. R.; Knaus, E. E. Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual Inhibitors of cyclooxygenases and 5-lipoxygenase. Bioorg. Med. Chem. Lett. 2010, 20, 2168– 2173, DOI: 10.1016/j.bmcl.2010.02.040[Crossref], [PubMed], [CAS], Google Scholar203bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjslGmtrg%253D&md5=10042762346b7c2e0e9794d9c470f163Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual inhibitors of cyclooxygenases and 5-lipoxygenaseYu, Gang; Praveen Rao, P. N.; Chowdhury, Morshed A.; Abdellatif, Khaled R. A.; Dong, Ying; Das, Dipankar; Velazquez, Carlos A.; Suresh, Mavanur R.; Knaus, Edward E.Bioorganic & Medicinal Chemistry Letters (2010), 20 (7), 2168-2173CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A new group of acetic acid and propionic acid regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compds. exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isoenzyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, i.e., absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid (I) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Mol. modeling (docking) studies showed that the highly electroneg. CHF2 substituent present in I, that showed a modest selectivity for the COX-2 isoenzyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO2NH2) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region contg. the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.
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], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvF2nsLY%253D&md5=69f0655b7ff06aee79054c470aefe66cFluorinated Phosphonates: Synthesis and Biomedical ApplicationRomanenko, Vadim D.; Kukhar, Valery P.Chemical Reviews (Washington, DC, United States) (2006), 106 (9), 3868-3935CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The synthesis, fundamental chem. properties, and biomedical uses of the phosphonic acid derivs. that bear at least one F substituent on the organyl moiety are the subject of this review, which is organized as follows. The 1st part is a survey of synthetic methods used for the prepn. of fluorinated phosphonates. The 2nd part consists of a presentation of the different types of fluorophosphonates having significant biol. importance. The 3rd part describes the use of fluorinated phosphonates in biomedical studies (e.g. enzyme inhibitors, catalytic antibodies, antiviral agents, antitumor agents, anti-platelet-aggregation agents). Discussion of basic aspects of phosphonate and organofluorine chem. is reduced to min. to avoid redundancy to the long series of papers already published in journals and books. Also no particular attention will be paid to subjects that have recently been reviewed. In such cases, only the most important trends are briefly summarized. Literature coverage for the review extends up to Apr. 2006. - 205(a) Blackburn, G. M.; Kent, D. E. A novel synthesis of R- and γ-fluoroalkylphosphonates. J. Chem. Soc., Chem. Commun. 1981, 511– 513, DOI: 10.1039/C39810000511 .(b) Blackburn, G. M.; England, D. A.; Kolkmann, F. Monofluoro and difluoro-methylenebisphosphonic acids: isopolar analogues of pyrophosphoric acid. J. Chem. Soc., Chem. Commun. 1981, 930– 932, DOI: 10.1039/c39810000930
- 206(a) Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jaina, S. C. The difluoromethylenephosphonate moiety as a phosphate mimic: X-ray structure of 2-amino-1,1,-difluoroethylphosphonic acid. J. Chem. Soc., Chem. Commun. 1990, 1053– 1054, DOI: 10.1039/c39900001053 .(b) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard, J. A. K. Synthesis of monofluoro- and difluoro- methylenephopshonate analogues of sn-glycerol-3-phosphate as substrates for glycerol-3-phosphate dehydrogenase and the X-ray structure of the fluoromethylenephosphonate moiety. Tetrahedron 1996, 52, 165– 176, DOI: 10.1016/0040-4020(95)00890-K .(c) O’Hagan, D.; Rzepa, H. S. Some influences of fluorine in bioorganic chemistry. Chem. Commun. 1997, 645– 652, DOI: 10.1039/a604140j[Crossref], [CAS], Google Scholar.206chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXislGlu7g%253D&md5=6d37429e3baff14d46d1d24355eb2d86Some influences of fluorine in bioorganic chemistryO'Hagan, David; Rzepa, Henry S.Chemical Communications (Cambridge) (1997), (7), 645-652CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review with 76 refs. The stereochem. outcome on processing fluorinated substrate analogs by enzymes can often be controlled by electronic and stereoelectronic factors assocd. with the fluorine atoms. Interpreting or predicting the behavior of fluorinated compds. is complex and has led to the term flustrates (fluorine-contg. substrates) being coined. However, a greater appreciation of the electronic and stereoelectronic properties of org. fluorine renders the behavior of these compds. more interpretable.(d) Thatcher, G. R. J.; Campbell, A. S. Phosphonates as mimics of phosphate biomolecules: Ab initio calculations on tetrahedral ground states and pentacoordinate intermediates for phosphoryl transfer. J. Org. Chem. 1993, 58, 2272– 2281, DOI: 10.1021/jo00060a050
- 207Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. New prospects toward the synthesis of difluoromethylated phosphate mimics. Chem. - Eur. J. 2016, 22, 10284– 10293, DOI: 10.1002/chem.201601310[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGjurnM&md5=8ff2358df5c30d58ce2f1f970a6623a8New Prospects toward the Synthesis of Difluomethylated Phosphate MimicsIvanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, ThomasChemistry - A European Journal (2016), 22 (30), 10284-10293CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review of the prepn., reactions and biolical activities of difluoromethylated phosphonate-contg. mols. The difluoromethyl phosphonate motif plays a crucial role in the development of bioactive mols. as it is considered as a phosphate bioisoster. Since 2010, a renewal of interest to enlarge the panel of reactions to access these difluoromethylated phosphonate-contg. mols. was witnessed. This Concept article charts the recent progress that was made.
- 208(a) Bialy, L.; Waldmann, H. Inhibitors of protein tyrosine phosphatases: next-generation drugs?. Angew. Chem., Int. Ed. 2005, 44, 3814– 3839, DOI: 10.1002/anie.200461517[Crossref], [CAS], Google Scholar.208ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFGisr8%253D&md5=a8bcd03851b638cc6d3e6ab2466eb97bInhibitors of protein tyrosine phosphatases: Next-generation drugs?Bialy, Laurent; Waldmann, HerbertAngewandte Chemie, International Edition (2005), 44 (25), 3814-3839CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The protein tyrosine phosphatases (PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurol. disorders and diabetes. Consequently, PTPs have emerged as promising targets for therapeutic intervention in recent years. In this review, general aspects of PTPs and the development of small-mol. inhibitors of PTPs by both academic research groups and pharmaceutical companies are discussed. Different strategies have been successfully applied to identify potent and selective inhibitors. These studies constitute the basis for the future development of PTP inhibitors as drugs.(b) Combs, A. P. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J. Med. Chem. 2010, 53, 2333– 2344, DOI: 10.1021/jm901090b[ACS Full Text
], [CAS], Google Scholar208bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFektLzJ&md5=700b2a519c670e1bd9cb41af271d62aeRecent Advances in the Discovery of Competitive Protein Tyrosine Phosphatase 1B Inhibitors for the Treatment of Diabetes, Obesity, and CancerCombs, Andrew P.Journal of Medicinal Chemistry (2010), 53 (6), 2333-2344CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. - 209(a) Smyth, M. S.; Ford, H., Jr.; Burke, T. R., Jr. A general method for the preparation of benzylic R,R-difluorophosphonic acids; nonhydrolyzable mimetics of phosphotyrosine. Tetrahedron Lett. 1992, 33, 4137– 4140, DOI: 10.1016/S0040-4039(00)74672-7 .(b) Ivanova, M. V.; Bayle, A.; Besset, T.; Poisson, T.; Pannecoucke, X. Copper-mediated formation of aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates: a general approach to fluorinated phosphate mimics. Angew. Chem., Int. Ed. 2015, 54, 13406– 13410, DOI: 10.1002/anie.201507130[Crossref], [CAS], Google Scholar.209bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2nsrbP&md5=3d705f0582fc16afbb0df60329c9e715Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate MimicsIvanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Poisson, Thomas; Pannecoucke, XavierAngewandte Chemie, International Edition (2015), 54 (45), 13406-13410CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodol. using TMSCF2PO(OEt)2, iodonium salts and a Cu salt provided a straightforward manifold to reach these highly relevant products. The reaction proved to be highly functional group tolerant and proceeded under mild conditions, giving the corresponding products in good to excellent yields. This method represents the 1st general synthetic route to this important class of fluorinated scaffolds, which are well-recognized as in vivo stable phosphate surrogates.(c) Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. Copper-mediated introduction of the CF2PO(OEt)2 motif: scope and limitations. Chem. - Eur. J. 2017, 23, 17318– 17338, DOI: 10.1002/chem.201703542[Crossref], [PubMed], [CAS], Google Scholar209chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWntbzP&md5=d46a0ae6241cd7b5e38ddb34f20cfdd5Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope and LimitationsIvanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, ThomasChemistry - A European Journal (2017), 23 (68), 17318-17338CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Herein, a general procedure to access CF2PO(OEt)2-contg. mols. is reported. The reagent CuCF2PO(OEt)2 is accessible by a simple protocol and a broad range of substrates can be functionalized. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated mols. at room temp. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalized, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF2PO(OEt)2-contg. mols.
- 210(a) Panigrahi, K.; Eggen, M.; Maeng, J.-H.; Shen, Q.; Berkowitz, D. B. The α,α-difluorinated phosphonate L-pSer-analogue: an accessible chemical tool for studying kinase-dependent signal transduction. Chem. Biol. 2009, 16, 928– 936, DOI: 10.1016/j.chembiol.2009.08.008[Crossref], [PubMed], [CAS], Google Scholar.210ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFynsL3I&md5=a0ece823d48b1197f6a4f16a52f9a3a9The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal TransductionPanigrahi, Kaushik; Eggen, MariJean; Maeng, Jun-Ho; Shen, Quanrong; Berkowitz, David B.Chemistry & Biology (Cambridge, MA, United States) (2009), 16 (9), 928-936CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)A review. This overview focuses on the (α,α-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chem. biol. tools are discussed, organized by method of PCF2-C bond formation. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chem. biol. approach include the regulation of p53 tumor suppressor protein activity and of melatonin prodn. Given these successes, the future is bright for the use of such "teflon phospho-amino acid mimics" to map kinase-based signaling pathways.(b) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a phosphoserine mimetic prodrug with potent 14–3-3 protein inhibitory activity. Chem. Biol. 2012, 19, 764– 771, DOI: 10.1016/j.chembiol.2012.05.011[Crossref], [PubMed], [CAS], Google Scholar210bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptVKlsLo%253D&md5=712ae5cf745751cf2ccbc3c585ff96caSynthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory ActivityArrendale, Allison; Kim, Keunho; Choi, Jun Young; Li, Wei; Geahlen, Robert L.; Borch, Richard F.Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (6), 764-771CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs contg. phosphorylated serine and threonine residues. To create small mols. that inhibit such interactions, we developed methodol. for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small mol. inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concns. when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concn.-dependent manner that correlates well with its ability to inhibit cell growth. This methodol. can be applied to target a variety of proteins contg. phosphoserine and other phosphoamino acid binding domains.
- 211(a) Rye, C. S.; Baell, J. B. Phosphate isosteres in medicinal chemistry. Curr. Med. Chem. 2005, 12, 3127– 3141, DOI: 10.2174/092986705774933452[Crossref], [PubMed], [CAS], Google Scholar.211ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlSqsrbJ&md5=585a42ff8051b687939a70055612fab5Phosphate isosteres in medicinal chemistryRye, C. S.; Baell, J. B.Current Medicinal Chemistry (2005), 12 (26), 3127-3141CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. The phosphate group is at the heart of an enormous no. of biol. processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biol. activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognize the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chem. research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognizing domains such as Src homol. 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilization of the phosphate moiety as part of an inhibitor is severely limited by the enzymic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favorably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylene phosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the mol. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chem., covering roughly the past four years.(b) Elliott, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. The use of phosphate bioisosteres in medicinal chemistry and chemical biology. MedChemComm 2012, 3, 735– 751, DOI: 10.1039/c2md20079a[Crossref], [CAS], Google Scholar.211bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsVShsr0%253D&md5=6a6a7b53bd71aaa052df27cefae38036The use of phosphate bioisosteres in medicinal chemistry and chemical biologyElliott, Thomas S.; Slowey, Aine; Ye, Yulin; Conway, Stuart J.MedChemComm (2012), 3 (7), 735-751CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. Phosphate and pyrophosphate groups play a central role in cellular signalling and consequently are of great interest to both medicinal chemists and chem. biologists. However, the design of mols. that can interfere with phosphate-based processes is recognized as a significant challenge, esp. when the resulting compds. must show good cellular penetration and stability. Herein, we have reviewed the full range of phosphate bioisosteres currently reported and provided the context of their deployment. We aim to provide a useful ref. for medicinal chemists and chem. biologists who are engaged in the design of mols. that target phosphate-binding proteins.(c) Zhang, Y.; Borrel, A.; Ghemtio, L.; Regad, L.; Boije af Gennäs, G.; Camproux, A.-C.; Yli-Kauhaluoma, J.; Xhaard, H. Structural isosteres of phosphate groups in the protein data bank. J. Chem. Inf. Model. 2017, 57, 499– 516, DOI: 10.1021/acs.jcim.6b00519[ACS Full Text
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- 215Hakogi, T.; Yamamoto, T.; Fujii, S.; Ikeda, K.; Katsumura, S. Synthesis of sphingomyelin difluoromethylene analogue. Tetrahedron Lett. 2006, 47, 2627– 2630, DOI: 10.1016/j.tetlet.2006.02.018[Crossref], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xitlarsbo%253D&md5=a50d891bb2c469fbfb8e2fadf044ee0aSynthesis of sphingomyelin difluoromethylene analogHakogi, Toshikazu; Yamamoto, Tetsuya; Fujii, Shinobu; Ikeda, Kiyoshi; Katsumura, ShigeoTetrahedron Letters (2006), 47 (15), 2627-2630CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)As a new sphingomyelinase inhibitor, a novel sphingomyelin CF2 analog was designed and synthesized. One key step of this synthesis is the very mild hydrolysis of the oxazolidinone ring of methylphosphonate I, a suitable intermediate for the introduction of a di-Et difluoro-methylphosphonate group, by utilizing the characteristic electron withdrawing nature of the group at the oxazolidinone ring in an alc. solvent to produce the corresponding carbonate attaching at the secondary hydroxy group. The synthesized CF2 analog inactivated toward B. cereus sphingomyelinase with nearly the same attitude as the nitrogen analog that we previously reported.
- 216(a) Lapierre, J.; Ahmed, V.; Chen, M.-J.; Ispahany, M.; Guillemette, J. G.; Taylor, S. D. The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 151– 155, DOI: 10.1016/j.bmcl.2003.09.089[Crossref], [PubMed], [CAS], Google Scholar.216ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvVWntLY%253D&md5=951b12f71bdbd87fd99a02ce879f955dThe difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitorsLapierre, Jennifer; Ahmed, Vanessa; Chen, Mei-Jin; Ispahany, Mehdi; Guillemette, J. Guy; Taylor, Scott D.Bioorganic & Medicinal Chemistry Letters (2004), 14 (1), 151-155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)Several estrone sulfate and estradiol sulfate analogs, in which the sulfate group was replaced with an α,α-difluoromethylenesulfonate group or an α,α-difluoromethylenetetrazole group, were examd. as inhibitors of steroid sulfatase (STS). These compds. were 4.5-10.5 times more potent than their non-fluorinated analogs. Moreover, the presence of the fluorines changed the mode of inhibition from mixed to competitive. The inhibitor bearing the α,α-difluoromethylenetetrazole group exhibited an affinity for STS approaching that of the natural STS substrate, estrone sulfate. Possible reasons for the enhanced affinity of the fluorinated compds. compared to their non-fluorinated counterparts are discussed.(b) Liu, Y.; Ahmed, V.; Hill, B.; Taylor, S. D. Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor. Org. Biomol. Chem. 2005, 3, 3329– 3335, DOI: 10.1039/b508852f[Crossref], [PubMed], [CAS], Google Scholar216bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpsFWnsbo%253D&md5=3cf8ae7e607a93f7d35b8677bcf76625Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitorLiu, Yong; Ahmed, Vanessa; Hill, Bryan; Taylor, Scott D.Organic & Biomolecular Chemistry (2005), 3 (18), 3329-3335CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analog bearing an α,α-difluorosulfonamide moiety at the 3-position on the A-ring, I, was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pKa of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was detd. to be 8.05 using 19F NMR. I is a reversible inhibitor with a Ki similar to that of its sulfonate analog at pH 7.0. It is more potent than its nonfluorinated sulfonamide analog and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.
- 217(a) Maltais, R.; Poirier, D. Steroid sulfatase inhibitors: a review covering the promising 2000–2010 decade. Steroids 2011, 76, 929– 948, DOI: 10.1016/j.steroids.2011.03.010 .(b) Mostafa, Y. A.; Taylor, S. D. Steroid derivatives as inhibitors of steroid sulfatase. J. Steroid Biochem. Mol. Biol. 2013, 137, 183– 198, DOI: 10.1016/j.jsbmb.2013.01.013[Crossref], [PubMed], [CAS], Google Scholar217bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXislyltbk%253D&md5=920cbdc85ea6cd9680f01b62330f9a1bSteroid derivatives as inhibitors of steroid sulfataseMostafa, Yaser A.; Taylor, Scott D.Journal of Steroid Biochemistry and Molecular Biology (2013), 137 (), 183-198CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)A review. Sulfated steroids function as a storage reservoir of biol. active steroid hormones. The sulfated steroids themselves are biol. inactive and only become active in vivo when they are converted into their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS are considered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast, prostate and endometrial cancer. The present review summarizes steroid derivs. as inhibitors of STS covering the literature from the early years of STS inhibitor development to Oct. of 2012. A brief discussion of the function, structure and mechanism of STS and its role in estrogen receptor-pos. (ER+) hormone-dependent breast cancer is also presented.This article is part of a Special Issue entitled "Synthesis and biol. testing of steroid derivs. as inhibitors".
- 218Kotoris, C. K.; Chen, M.-J.; Taylor, S. D. Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. Lett. 1998, 8, 3275– 3280, DOI: 10.1016/S0960-894X(98)00598-8
- 219Lomelino, C.; McKenna, R. Carbonic anhydrase inhibitors: a review on the progress of patent literature (2011–2016). Expert Opin. Ther. Pat. 2016, 26, 947– 956, DOI: 10.1080/13543776.2016.1203904[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFCrtb3K&md5=76c935b7b64cbe4d9c8e7710ee68bc1dCarbonic anhydrase inhibitors: a review on the progress of patent literature (2011-2016)Lomelino, Carrie; McKenna, RobertExpert Opinion on Therapeutic Patents (2016), 26 (8), 947-956CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)Introduction: A large area of carbonic anhydrase (CA) research focuses on the inhibition of human CA IX and CA XII, as these isoforms have been designated as biomarkers and therapeutic targets for various cancer types. Areas covered: Recently, the majority of CA inhibitor (CAI) patents cover compd. design, synthesis, and delivery methods for the treatment of glaucoma and cancer. The anal. of included patents highlights the need for isoform specific inhibitors. This review covers the patents of medically relevant carbonic anhydrase inhibitors between 2011-2016. Expert opinion: The improvement of structure-based drug design methods and access to the crystal structures of human CA isoforms have improved inhibitor development. This progress can be obsd. in relation to the selective inhibition of CA IX for cancer treatments, with one inhibitor in clin. trials. However, the design of nonclassical CAIs is essential to further improve isoform specificity and prevent sulfur allergies.
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- 222Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFemsbY%253D&md5=478b70744312c01d3a43cf435d9598dePredicting and tuning physicochemical properties in lead optimization: amine basicitiesMorgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, KlausChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
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- 225Huang, H.; Hutta, D. A.; Rinker, J. M.; Hu, H.; Parsons, W. H.; Schubert, C.; DesJarlais, R. L.; Crysler, C. S.; Chaikin, M. A.; Donatelli, R. R.; Chen, Y.; Cheng, D.; Zhou, Z.; Yurkow, E.; Manthey, C. L.; Player, M. R. Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J. Med. Chem. 2009, 52, 1081– 1099, DOI: 10.1021/jm801406h
- 226Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam, C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.; Slingsby, B. P.; Swarbrick, M. E. Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain. Bioorg. Med. Chem. Lett. 2010, 20, 465– 468, DOI: 10.1016/j.bmcl.2009.11.117[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsF2itb%252FN&md5=9848ef9b152eee020cfb77960e820728Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory painGleave, Robert J.; Beswick, Paul J.; Brown, Andrew J.; Giblin, Gerard M. P.; Goldsmith, Paul; Haslam, Carl P.; Mitchell, William L.; Nicholson, Neville H.; Page, Lee W.; Patel, Sadhana; Roomans, Susan; Slingsby, Brian P.; Swarbrick, Martin E.Bioorganic & Medicinal Chemistry Letters (2010), 20 (2), 465-468CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of 3-amino-6-aryl-pyridazines have been identified as CB2 agonists with high efficacy and selectivity against the CB1 receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analog I, a compd. with high potency in an in vivo model of inflammatory pain.
- 227(a) Sundar, B. G.; Bailey, T. R.; Dunn, D.; Hostetler, G. A.; Chatterjee, S.; Bacon, E. R.; Yue, C.; Schweizer, D.; Aimone, L. D.; Gruner, J. A.; Lyons, J.; Raddatz, R.; Lesur, B. Novel morpholine ketone analogs as potent histamine H3 receptor inverse agonists with wake activity. Bioorg. Med. Chem. Lett. 2012, 22, 1546– 1549, DOI: 10.1016/j.bmcl.2012.01.004 .(b) Zulli, A.; Aimone, L. D.; Mathiasen, J. R.; Gruner, J. A.; Raddatz, R.; Bacon, E. R.; Hudkins, R. L. Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists. Bioorg. Med. Chem. Lett. 2012, 22, 2807– 2810, DOI: 10.1016/j.bmcl.2012.02.081
- 228Garton, N. S.; Barker, M. D.; Davis, R. P.; Douault, C.; Hooper-Greenhill, E.; Jones, E.; Lewis, H. D.; Liddle, J.; Lugo, D.; McCleary, S.; Preston, A. G. S.; Ramirez-Molina, C.; Neu, M.; Shipley, T. J.; Somers, D. O.; Watson, R. J.; Wilson, D. M. Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 4606– 4612, DOI: 10.1016/j.bmcl.2016.08.070
- 229Ahmad, S.; Washburn, W. N.; Hernandez, A. S.; Bisaha, S.; Ngu, K.; Wang, W.; Pelleymounter, M. A.; Longhi, D.; Flynn, N.; Azzara, A. V.; Rohrbach, K.; Devenny, J.; Rooney, S.; Thomas, M.; Glick, S.; Godonis, H.; Harvey, S.; Zhang, H.; Gemzik, B.; Janovitz, E. B.; Huang, C.; Zhang, L.; Robl, J. A.; Murphy, B. J. Synthesis and antiobesity properties of 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): a highly efficacious melanin concentrating hormone receptor 1 (MCHR1) inhibitor. J. Med. Chem. 2016, 59, 8848– 8858, DOI: 10.1021/acs.jmedchem.6b00676
- 230(a) Deliencourt-Godefroy, G.; Lopes, L. Family of Aryl, Heteroaryl, O-Aryl and O-Heteroaryl Carbasugars. World Patent Application WO 2012/160218, Nov. 29, 2012.(b) Chen, Z.-H.; Wang, R.-W.; Qing, F.-L. Synthesis and biological evaluation of SGLT2 inhibitors: gem-difluoromethylenated dapagliflozin analogs. Tetrahedron Lett. 2012, 53, 2171– 2176, DOI: 10.1016/j.tetlet.2012.02.062
- 231(a) Berry, C. B.; Bubser, M.; Jones, C. K.; Hayes, J. P.; Wepy, J. A.; Locuson, C. W.; Daniels, J. S.; Lindsley, C. W.; Hopkins, C. R. Discovery and characterization of ML398, a potent and selective antagonist of the D4 receptor with in vivo activity. ACS Med. Chem. Lett. 2014, 5, 1060– 1064, DOI: 10.1021/ml500267c .(b) Witt, J. O.; McCollum, A. L.; Hurtado, M. A.; Huseman, E. D.; Jeffries, D. E.; Temple, K. J.; Plumley, H. C.; Blobaum, A. L.; Lindsley, C. W.; Hopkins, C. R. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists. Bioorg. Med. Chem. Lett. 2016, 26, 2481– 2488, DOI: 10.1016/j.bmcl.2016.03.102
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- 233Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Direct synthesis of fluorinated heteroarylether bioisosteres. Angew. Chem., Int. Ed. 2013, 52, 3949– 3952, DOI: 10.1002/anie.201300763[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsVOhu7k%253D&md5=14e8d7c1d2f0494de4b5f78a11f5aa6cDirect Synthesis of Fluorinated Heteroarylether BioisosteresZhou, Qianghui; Ruffoni, Alessandro; Gianatassio, Ryan; Fujiwara, Yuta; Sella, Eran; Shabat, Doron; Baran, Phil S.Angewandte Chemie, International Edition (2013), 52 (14), 3949-3952CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A modular synthesis of reagents (e.g. sodium 1,1-difluoroethylsulfinate) that can be used for direct incorporation of 1,1-difluoroalkyl groups onto various heterocycles is reported. The scope and generality of the incorporation of difluoroalkyl groups is exemplified with the 1,1-difluoroethyl group, and a proof of principle is shown for a general synthesis of fluorinated heteroaryl ether bioisosteres.
- 234Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Potent, Highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. J. Am. Chem. Soc. 2010, 132, 14229– 14238, DOI: 10.1021/ja106175q[ACS Full Text
], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmt7nP&md5=7d9f72450e01f2dd53e4c07eb4e88eedPotent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide SynthaseXue, Fengtian; Li, Huiying; Delker, Silvia L.; Fang, Jianguo; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.Journal of the American Chemical Society (2010), 132 (40), 14229-14238CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compds., e.g., I, contg. a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compds., (S,S) vs. (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compds. with monocationic character under physiol. pH conditions. Biol. evaluations have led to a nNOS inhibitor with a Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calcns. indicated that the low pKa NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compd. to the parent mol. shows 22% for the difluorinated compd. vs. essentially no oral bioavailability for the parent compd. This indicates that the goal of this research to make compds. with only one protonated nitrogen atom at physiol. pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished. - 235Anderson, M. O.; Zhang, J.; Liu, Y.; Yao, C.; Phuan, P.-W.; Verkman, A. S. Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J. Med. Chem. 2012, 55, 5942– 5950, DOI: 10.1021/jm300491y[ACS Full Text
], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1Snur4%253D&md5=a1140ee5f316022648a8140fbd6607dfNanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-BAnderson, Marc O.; Zhang, Jicheng; Liu, Yan; Yao, Chenjuan; Phuan, Puay-Wah; Verkman, A. S.Journal of Medicinal Chemistry (2012), 55 (12), 5942-5950CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic ('urearetic') mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC50 = 25.1 nM and reduced urinary concn. in mice (Yao et al. J. Am. Soc. Nephrol., in press). Here, we analyzed com. available analogs of (I) to establish a structure-activity series and synthesized a targeted library of 11 analogs to identify potent, metabolically stable UT-B inhibitors. The best compd., {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, (II), had IC50 of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, resp., and ∼40-fold improved in vitro metabolic stability compared to I. In mice, II accumulated in kidney and urine and reduced max. urinary concn. Triazolothienopyrimidine may be useful for therapy of diuretic-refractory edema in heart and liver failure. - 236Piotrowski, D. W.; Futatsugi, K.; Warmus, J. S.; Orr, S. T.M.; Freeman-Cook, K. D.; Londregan, A. T.; Wei, L.; Jennings, S. M.; Herr, M.; Coffey, S. B.; Jiao, W.; Storer, G.; Hepworth, D.; Wang, J.; Lavergne, S. Y.; Chin, J. E.; Hadcock, J. R.; Brenner, M. B.; Wolford, A. C.; Janssen, A. M.; Roush, N. S.; Buxton, J.; Hinchey, T.; Kalgutkar, A. S.; Sharma, R.; Flynn, D. A. Identification of tetrahydropyrido[4,3-d]pyrimidine amides as a new class of orally bioavailable TGR5 agonists. ACS Med. Chem. Lett. 2013, 4, 63– 68, DOI: 10.1021/ml300277t[ACS Full Text
], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1GlsrfP&md5=7806a5272db5d3b6bc935f6df38a2b04Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 AgonistsPiotrowski, David W.; Futatsugi, Kentaro; Warmus, Joseph S.; Orr, Suvi T. M.; Freeman-Cook, Kevin D.; Londregan, Allyn T.; Wei, Liuqing; Jennings, Sandra M.; Herr, Michael; Coffey, Steven B.; Jiao, Wenhua; Storer, Gregory; Hepworth, David; Wang, Jian; Lavergne, Sophie Y.; Chin, Janice E.; Hadcock, John R.; Brenner, Martin B.; Wolford, Angela C.; Janssen, Ann M.; Roush, Nicole S.; Buxton, Joanne; Hinchey, Terri; Kalgutkar, Amit S.; Sharma, Raman; Flynn, Declan A.ACS Medicinal Chemistry Letters (2013), 4 (1), 63-68CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biol. target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of I, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that I could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5. - 237(a) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in drug design: a case study with fluoroanisoles. ChemMedChem 2015, 10, 715– 726, DOI: 10.1002/cmdc.201402555[Crossref], [PubMed], [CAS], Google Scholar.237ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvVWku7Y%253D&md5=45dbead703594c31581cc6c7e62d1b81Fluorine in Drug Design: A Case Study with FluoroanisolesXing, Li; Blakemore, David C.; Narayanan, Arjun; Unwalla, Ray; Lovering, Frank; Denny, R. Aldrin; Zhou, Huanyu; Bunnage, Mark E.ChemMedChem (2015), 10 (4), 715-726CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addn. to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochem. and pharmacokinetic properties. Anal. of anisole and fluoroanisole matched mol. pairs in the Pfizer corporate database reveals interesting trends: (1) PhOCF3 increases log D by ∼1 log unit over PhOCH3 compds.; (2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and (3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3. Emerging from the investigation, difluoroanisole (PhOCF2H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, the anal. suggests PhOCF2H may be a more attractive alternative, and greater exploitation of this motif is recommended.(b) Jeschke, P.; Baston, E.; Leroux, F. R. α-Fluorinated ethers as “exotic” entity in medicinal chemistry. Mini-Rev. Med. Chem. 2007, 7, 1027– 1034, DOI: 10.2174/138955707782110150[Crossref], [PubMed], [CAS], Google Scholar237bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1Sjs7fN&md5=ad28d99858f35257c9bec151e6a4db9aα-Fluorinated ethers as "exotic" entity in medicinal chemistryJeschke, Peter; Baston, Eckhard; Leroux, Frederic R.Mini-Reviews in Medicinal Chemistry (2007), 7 (10), 1027-1034CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacol. drugs, neurol. drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chem.
- 238(a) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis. J. Chem. Inf. Model. 2008, 48, 1– 24, DOI: 10.1021/ci7002494[ACS Full Text.
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- 240Hartz, R. A.; Ahuja, V. T.; Rafalski, M.; Schmitz, W. D.; Brenner, A. B.; Denhart, D. J.; Ditta, J. L.; Deskus, J. A.; Yue, E. W.; Arvanitis, A. G.; Lelas, S.; Li, Y.-W.; Molski, T. F.; Wong, H.; Grace, J. E.; Lentz, K. A.; Li, J.; Lodge, N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Mattson, R. J.; Bronson, J. J.; Macor, J. E. In vitro intrinsic clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. J. Med. Chem. 2009, 52, 4161– 4172, DOI: 10.1021/jm900302q[ACS Full Text
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- 243(a) Altomonte, S.; Zanda, M. Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules. J. Fluorine Chem. 2012, 143, 57– 93, DOI: 10.1016/j.jfluchem.2012.06.030[Crossref], [CAS], Google Scholar.243ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyktLzF&md5=cc717bde9781e01cf6d7e5d48e479154Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic moleculesAltomonte, Stefano; Zanda, MatteoJournal of Fluorine Chemistry (2012), 143 (), 57-93CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A review. The pentafluorosulphanyl group (SF5) is a highly stable chem. function which has been attracting a great deal of interest owing to its peculiar chem., structural, physicochem. and biol. properties. Progress in the area of SF5-compds. has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF5-group into org. mols. However, recent synthetic progress, the availability of some SF5-building blocks from com. suppliers and the discovery of interesting properties of SF5-substituted mols. in materials science, biol. and drug discovery are giving new momentum to research in this fascinating area of fluorine chem. Synthesis, reactivity and biol. properties of SF5-substituted org. mols. are herein reviewed with an emphasis on the work published after year 2000.(b) Sowaileh, M. F.; Hazlitt, R. A.; Colby, D. A. Application of the pentafluorosulfanyl group as a bioisosteric replacement. ChemMedChem 2017, 12, 1481– 1490, DOI: 10.1002/cmdc.201700356[Crossref], [PubMed], [CAS], Google Scholar243bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2ju7fK&md5=d7ebb1fd3f7f0f380f16608a16ffefc6Application of the Pentafluorosulfanyl Group as a Bioisosteric ReplacementSowaileh, Munia F.; Hazlitt, Robert A.; Colby, David A.ChemMedChem (2017), 12 (18), 1481-1490CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The success of fluorinated mols. in drug design has led medicinal chemists to search for new fluorine-contg. substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiol. conditions and displays unique phys. and chem. properties. There are currently few synthetic methods to install the SF5 group, yet efforts to integrate this group into lead optimization continue unabated. Typically, the SF5 group has been used as a replacement for trifluoromethyl, tert-Bu, halogen, or nitro groups. In this review, the use of the SF5 group as a bioisosteric replacement for each of these three functionalities is compared and contrasted across various groups of biol. active mols. The organization and presentation of these data should be instructive to medicinal chemists considering to design synthetic strategies to access SF5-substituted mols.
- 244(a) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien, E. J. Aromatic substituent constants for structure-activity correlations. J. Med. Chem. 1973, 16, 1207– 1216, DOI: 10.1021/jm00269a003[ACS Full Text.
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- 246Rouxel, C.; Le Droumaguet, C.; Macé, Y.; Clift, S.; Mongin, O.; Magnier, E.; Blanchard-Desce, M. Octupolar derivatives functionalized with superacceptor peripheral groups: synthesis and evaluation of the electron-withdrawing ability of potent unusual groups. Chem. - Eur. J. 2012, 18, 12487– 12497, DOI: 10.1002/chem.201103460[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1aqt7rF&md5=15e7452af62d8368de0f567503e36270Octupolar Derivatives Functionalized with Superacceptor Peripheral Groups: Synthesis and Evaluation of the Electron-Withdrawing Ability of Potent Unusual GroupsRouxel, Cedric; Le Droumaguet, Celine; Mace, Yohan; Clift, Sophie; Mongin, Olivier; Magnier, Emmanuel; Blanchard-Desce, MireilleChemistry - A European Journal (2012), 18 (39), 12487-12497, S12487/1-S12487/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Novel tripodal derivs. with a triphenylamine core and that bear "superacidifiers" (i.e., fluorinated sulfoximinyl blocks) or novel sulfiliminyl moieties as peripheral groups were synthesized. These new chromophores show strong absorption in the near-UV region and emission in the visible region. The fluorinated sulfoximinyl moieties were found to behave as potent auxochromic and electron-withdrawing (EW) groups, thus leading to red shifted absorption and emission. These moieties promote a core-to-periphery intramol. charge transfer (ctp-ICT) transition, the energy of which was found to be correlated to their EW strength. In this study, we provide evidence of a linear correlation between the Hammett const. (σp) values and the electronic gap between the ground and first excited state of the three-branched derivs. This in turn was used to derive σp values of fluorinated sulfoximinyl moieties. These EWGs show unprecedentedly high σp values, up to 1.45 relative to 0.8 for NO2. Also, by using this method, the sulfiliminyl moiety was shown to exhibit similar EW strength as NO2, while promoting improved transparency and soly. Finally, the superior EW strength of the fluorinated sulfoximine peripheral moieties was shown to induce significant enhancement of the two-photon absorption responses in the red near-IR region of the three-branched derivs. relative to similar octupoles that bear more usual strong EW groups. These characteristics (improved nonlinear responses or transparency) open new routes for the design of nonlinear optical (NLO) chromophores for optical limiting or electro-optical modulation. Such building blocks could also be of interest for optoelectronic applications, including the development of solar cells.
- 247(a) Bowden, R. D.; Comina, P. J.; Greenhall, M. P.; Kariuki, B. M.; Loveday, A.; Philp, D. A new method for the synthesis of aromatic sulfurpentafluorides and studies of the stability of the sulfurpentafluoride group in common synthetic transformations. Tetrahedron 2000, 56, 3399– 3408, DOI: 10.1016/S0040-4020(00)00184-8 .(b) Savoie, P. R.; Welch, J. T. Preparation and utility of organic pentafluorosulfanyl-containing compounds. Chem. Rev. 2015, 115, 1130– 1190, DOI: 10.1021/cr500336u[ACS Full Text.
], [CAS], Google Scholar247bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVWns73O&md5=1c445f254870e416ed116de454d08ccaPreparation and utility of organic pentafluorosulfanyl-containing compoundsSavoie, Paul R.; Welch, John T.Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 1130-1190CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review on prepn. of pentafluorosulfanyl-contg. compds. and their use in a variety of synthetic org. reactions.(c) von Hahmann, C. N.; Savoie, P. R.; Welch, J. T. Reactions of organic pentafluorosulfanyl-containing compounds. Curr. Org. Chem. 2015, 19, 1592– 1618, DOI: 10.2174/1385272819666150601211131[Crossref], [CAS], Google Scholar247chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFajsbzE&md5=59380a99635eb5976d54b98d708647c7Reactions of Organic Pentafluorosulfanyl-containing Compoundsvon Hahmann, Cortney N.; Savoie, Paul R.; Welch, John T.Current Organic Chemistry (2015), 19 (16), 1592-1618CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)A review. While significant attention was focused on the incorporation of fluorine in C-F bonds, or the introduction of a trifluoromethyl (CF3) groups, previously, the role of SF5 group was highlighted in this review. The SF5 group has a similar electron withdrawing effect as the CF3 group yet the SF5 group is significantly more lipophilic. Combining these properties resulted in the proclivity of SF5-contg. arenes to undergo displacement reactions. The hydrophobicity of the SF5-group was used to direct the conformation of SF5-contg. peptides. The profound dipole assocd. with pentafluorosulfanylation was successfully used to direct the stereochem. of the Staudinger reaction. The greater steric demand of the SF5 group relative to the CF3 group had dramatically effected the conformation of small mols. by encumbering rotational freedom. The influence of the SF5-group on the reactions of alkanes, alkenes, alkynes, arenes and various functional groups was reviewed. - 248Stump, B.; Eberle, C.; Schweizer, W. B.; Kaiser, M.; Brun, R.; Krauth-Siegel, R. L.; Lentz, D.; Diederich, F. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines. ChemBioChem 2009, 10, 79– 83, DOI: 10.1002/cbic.200800565
- 249Altomonte, S.; Baillie, G. L.; Ross, R. A.; Riley, J.; Zanda, M. The pentafluorosulfanyl group in cannabinoid receptor ligands: synthesis and comparison with trifluoromethyl and tert-butyl analogues. RSC Adv. 2014, 4, 20164– 20176, DOI: 10.1039/C4RA01212G[Crossref], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotVCiurw%253D&md5=cca2b696f2b483b7fd34aa8febdbb62eThe pentafluorosulfanyl group in cannabinoid receptor ligands: synthesis and comparison with trifluoromethyl and tert-butyl analoguesAltomonte, Stefano; Baillie, Gemma L.; Ross, Ruth A.; Riley, Jennifer; Zanda, MatteoRSC Advances (2014), 4 (39), 20164-20176CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)An array of cannabinoid ligands, substituted pyrazolecarboxamides I (R1 = 5-Br-2-thienyl, 4-ClC6H4; R2 = 2,4-Cl2C6H3, 2,4-F2C6H3; R3 = 3-F3CC6H4, 3-F5SC6H4, 3-t-BuC6H4, 4-F3CC6H4, 4-F5SC6H4, 4-t-BuC6H4) were efficiently synthesized. In general, the SF5-substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-Bu analogs. In terms of pharmacol. activity, SF5 pyrazoles generally showed slightly higher or equiv. CB1 receptor affinity (Ki), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-Bu analogs. Functional β-arrestin recruitment assays were used to det. equil. dissocn. consts. (Kb) and showed that all of the tested SF5 and CF3 compds. were CB1 neutral antagonists. These results confirm the possibility of successfully using an arom. SF5 group as a stable, synthetically accessible and effective bioisosteric analog of the electron-withdrawing CF3 group and possibly also of bulky aliph. groups for drug discovery and development applications.
- 250Sun, L.; Bera, H.; Chui, W. K. Synthesis of pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors of thymidine phosphorylase. Eur. J. Med. Chem. 2013, 65, 1– 11, DOI: 10.1016/j.ejmech.2013.03.063 .(b) Sun, L.; Li, J.; Bera, H.; Dolzhenko, A. V.; Chiu, G. N. C.; Chui, W. K. Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors. Eur. J. Med. Chem. 2013, 70, 400– 410, DOI: 10.1016/j.ejmech.2013.10.022
- 251Welch, J. T.; Lim, D. S. The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramine. Bioorg. Med. Chem. 2007, 15, 6659– 6666, DOI: 10.1016/j.bmc.2007.08.012[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVCisbfP&md5=5aa869f37f1c306c1879cbb75aa251fbThe synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramineWelch, John T.; Lim, Dong SungBioorganic & Medicinal Chemistry (2007), 15 (21), 6659-6666CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)The trifluoromethyl group of fluoxetine, fenfluramine, and norfenfluramine was substituted by the pentafluorosulfanyl group. On examn. of the efficacy of the pentafluorosulfanyl contg. compds. as inhibitors of 5-hydroxytryptamine receptors, it was found that substitution could lead to enhanced selectivity and in the case of the pentafluorosulfanyl analog of fenfluramine (I) it significantly enhanced potency against the 5-HT2b, 5-HT2c, and 5-HT6 receptors.
- 252Moraski, G. C.; Bristol, R.; Seeger, N.; Boshoff, H. I.; Tsang, P. S. Y.; Miller, M. J. Preparation and evaluation of potent pentafluorosulfanyl-substituted anti-tuberculosis compounds. ChemMedChem 2017, 12, 1108– 1115, DOI: 10.1002/cmdc.201700170
- 253Sansook, S.; Ocasio, C. A.; Day, I. J.; Tizzard, G. J.; Coles, S. J.; Fedorov, O.; Bennett, J. M.; Elkins, J. M.; Spencer, J. Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety. Org. Biomol. Chem. 2017, 15, 8655– 8660, DOI: 10.1039/C7OB02289A






